Cd73 inhibitors and uses thereof

ABSTRACT

Compounds that modulate CD73 activity, pharmaceutical compositions containing these compounds, and methods of using these compounds for treating diseases associated with CD73 activity are described herein.

CROSS-REFERENCE

This application claims the benefit of U.S. Provisional Application No.62/480,093, filed Mar. 31, 2017; U.S. Provisional Application No.62/526,265, filed Jun. 28, 2017; and U.S. Provisional Application No.62/648,625, filed Mar. 27, 2018, each incorporated herein by referencein its entirety.

BACKGROUND OF THE INVENTION

The immune system plays a critical role in the identification andelimination of neoplastic cells. Tumor cells use various mechanisms forevading the immune-mediated destruction of tumor cells. Among thosepathways, adenosine has been identified as a highly effective inhibitorof effector T cell function, and the enzyme CD73 (ecto-5′-nucleotidase,NT5E) has been identified as the enzyme responsible for generatingadenosine.

As tumor cells undergo cell death as a result of metabolic or hypoxicstress, they release intracellular stores of ATP into the extracellularspace. CD39 and CD73 are two ecto-enzymes that work together in atwo-step reaction to convert pro-inflammatory ATP into immunosuppressiveadenosine. CD39 hydrolyzes ATP into AMP, which is further hydrolyzed byCD73 into adenosine. Adenosine binds A2A receptors on T cells andactivates an intracellular signaling cascade leading to the suppressionof T cell activation and function. Activation of A2A receptors inhibitsIFNg production, as well as cytotoxic killing by CD8+ cells, and alsopromotes the differentiation of CD4+ cells into T-regulatory cells (Jin,et al. (2010) Cancer Res. 70:2245-55). Adenosine can also inhibitdifferentiation and function of dendritic cells, as well asproliferation and cytolytic function of NK cells (Hoskin, et. al. (2008)Int J Oncol 32:527-35). Activation of A2A receptors on tumor cells hasalso been suggested to promote tumor cell metastasis (Beavis et al.(2013) Proc Natl Acad Sci USA 110:14711-14716).

CD73 is expressed primarily in endothelial cells and a subset ofhematopoietic cells. CD73 expression has been observed in tumor cells inleukemia, bladder cancer, glioma, glioblastoma, lung cancer, ovariancancer, melanoma, prostate cancer, thyroid cancer, esophageal cancer andbreast cancer. CD73 expression in non-small-cell lung cancer andtriple-negative breast cancer is a prognostic marker for lower survivalrate (Inoue, et al. (2017) Oncotarget 5:8738-8751; and Loi, et al.(2013) Proc Natl Acad Sci USA 110:11091-11096). In the mouse, knock-downusing siRNA or overexpression of CD73 on mouse tumor cells can modulatetumor growth and metastasis (Beavis et al. (2013) Proc Natl Acad Sci USA110:14711-14716; Stagg et al. (2010) Cancer Res. 71:2892-2900; and Jinet al. (2010) Cancer Res. 70: 2245-55). CD73 plays a key role inpromoting tumor growth in the tumor microenvironment, as CD73−/− miceare protected from transplanted and spontaneous tumors (Stagg et al.(2010) Cancer Res. 71:2892-2900). Inhibition of CD73 has been proposedas a therapeutic approach for the treatment of cancer, and antibodies toCD73 have been reported to inhibit tumor growth by restoring immuneresponse to the tumors (Hay, et al. (2016) Oncoimmunology;5(8):e1208875).

SUMMARY OF THE INVENTION

A better understanding of the complex interactions between the immunesystem and tumors has allowed for the identification of key moleculesthat govern the tumor immune evasion. These findings have revitalizedinterest in cancer immunotherapeutics designed to overcome thesecheckpoint mechanisms. There is a need in the art for novel CD73 smallmolecule inhibitors. The present disclosure addresses this need byproviding CD73 inhibitors as described herein.

In certain aspects, the present disclosure provides a compound ofFormula (III):

or a pharmaceutically acceptable salt thereof, wherein:

W¹ is selected from N, NR⁸, CR⁶, and S;

W² and W³ are each independently selected from N and CR⁶;

W⁴ and W⁵ are each independently selected from N and C;

W⁶ is selected from N, CR⁶, and S;

-   -   wherein at least one of W¹, W², W³, W⁴, W⁵, and W⁶ is N, and        provided that:        -   when W¹, W², W³, W⁵, and W⁶ are N, W⁴ is not N; and        -   when either W¹ or W⁶ is S, the other is CR⁶;

R¹⁵ is selected from —NR¹R², —OR¹, —SR¹ and —CN; and C₃₋₁₂ memberedcarbocycle and 3- to 12-membered heterocycle, each of which isoptionally substituted with one or more R⁷;

R¹ is selected from hydrogen; and C₁₋₆ alkyl and C₃₋₁₂ carbocycle, eachof which is optionally substituted with one or more R⁷;

R² is selected from C₁₋₆ alkyl, C₃₋₁₂ carbocycle, 3- to 12-memberedheterocycle and benzyl, each of which is optionally substituted with oneor more R⁷; or

R¹ and R² are taken together with the nitrogen atom to which they areattached to form a 3- to 12-membered heterocycle, optionally substitutedwith one or more R⁷;

R³ is selected from hydrogen, halogen, cyano, —N(R⁸)₂ and —OR⁸; and C₁₋₆alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, 3- to 12-memberedheterocycle and benzyl, each of which is optionally substituted with oneor more R⁷;

A is selected from —O—, —S—, —S(═O)— and —S(═O)₂—;

X and Y are independently selected from —O— and —NR⁸—;

R⁴ and R⁵ are independently selected from:

-   -   hydrogen; and    -   C₁₋₆ alkyl, phenyl, and 3- to 12-membered heterocycle, each of        which is independently optionally substituted at each occurrence        with one or more substituents selected from halogen, —NO₂, —CN,        —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸,        —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂,        —NR⁸S(═O)₂NR⁹R¹⁰, —S—S—R⁸, —S—C(O)R⁸, —C(O)R⁸, —C(O)OR⁸,        —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸,        —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂,        —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂, —P(O)(R⁸)₂, —OP(O)(OR⁸)₂, ═O, ═S,        ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle; or

R⁴ and R⁵ are taken together with the atoms to which they are attachedto form a 3- to 12-membered heterocycle, optionally substituted with oneor more R⁷;

R⁶ is selected from hydrogen, halogen and cyano; and C₁₋₆ alkyl,optionally substituted with one or more R⁷;

R⁷ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸,        —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,        —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,        —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,        —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰,        —P(O)(OR⁸)₂, —P(O)(R⁸)₂, ═O, ═S, and ═N(R⁸);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁸,        —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to        12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁷ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁸, —SR⁸,        —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl;

R⁸ is independently selected at each occurrence from hydrogen; and C₁₋₂₀alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁹ and R¹⁰ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁷;

R¹³ is selected from hydrogen and C₁₋₆ alkyl; and

R¹⁴ is selected from hydrogen and R⁷.

In some embodiments, for a compound of Formula (III), W⁵ is N. In someembodiments, W⁵ is C. In some embodiments, one of W¹ or W⁶ is S. In someembodiments, W⁴ is N. In some embodiments, R¹³ is hydrogen. In someembodiments, R¹⁴ is selected from hydrogen and phenyl. In someembodiments, R¹⁵ is —NR¹R². In some embodiments, A is —O—. In someembodiments, A is selected from —S—, —S(═O)— and —S(═O)₂—.

In certain aspects, the present disclosure provides a compound ofFormula (II):

or a pharmaceutically acceptable salt thereof, wherein:

W¹, W² and W³ are each independently selected from N and CR⁶, wherein atleast one of W¹, W² and W³ is N;

R¹ is selected from hydrogen; and C₁₋₆ alkyl and C₃₋₁₂ carbocycle, eachof which is optionally substituted with one or more R⁷;

R² is selected from C₁₋₆ alkyl, C₃₋₁₂ carbocycle, 3- to 12-memberedheterocycle and benzyl, each of which is optionally substituted with oneor more R⁷; or

R¹ and R² are taken together with the nitrogen atom to which they areattached to form a 3- to 12-membered heterocycle, optionally substitutedwith one or more R⁷;

R³ is selected from hydrogen, halogen and cyano; and C₁₋₆ alkyl, C₃₋₁₂carbocycle, 3- to 12-membered heterocycle and benzyl, each of which isoptionally substituted with one or more R⁷;

A is selected from —S—, —S(═O)— and —S(═O)₂—;

X and Y are independently selected from —O— and —NR⁸—;

R⁴ and R⁵ are independently selected from:

-   -   hydrogen; and    -   C₁₋₆ alkyl and phenyl, each of which is independently optionally        substituted at each occurrence with one or more substituents        selected from halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰,        —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,        —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —S—S—R⁸, —S—C(O)R⁸, —C(O)R⁸,        —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰,        —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰,        —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂, —P(O)(R⁸)₂, —OP(O)(OR⁸)₂,        ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to 12-membered        heterocycle;

R⁶ is selected from hydrogen, halogen and cyano; and C₁₋₆ alkyl,optionally substituted with one or more R⁷;

R⁷ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸,        —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,        —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,        —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,        —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰,        —P(O)(OR⁸)₂, —P(O)(R⁸)₂, ═O, ═S, and ═N(R⁸);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁸,        —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to        12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁷ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁸, —SR⁸,        —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl;

R⁸ is independently selected at each occurrence from hydrogen; and C₁₋₂₀alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle; and

R⁹ and R¹⁰ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁷.

In certain aspects, the present disclosure provides a compound ofFormula (I):

or a pharmaceutically acceptable salt thereof, wherein:

W¹, W² and W³ are each independently selected from N and CR⁶, wherein atleast one of W¹, W² and W³ is N;

R¹ is selected from hydrogen; and C₁₋₆ alkyl and C₃₋₁₂ carbocycle, eachof which is optionally substituted with one or more R⁷;

R² is selected from C₁₋₆ alkyl, C₃₋₁₂ carbocycle, 3- to 12-memberedheterocycle and benzyl, each of which is optionally substituted with oneor more R⁷; or

R¹ and R² are taken together with the nitrogen atom to which they areattached to form a 3- to 12-membered heterocycle, optionally substitutedwith one or more R⁷;

R³ is selected from halogen and cyano; and C₁₋₆ alkyl, C₃₋₁₂ carbocycle,3- to 12-membered heterocycle and benzyl, each of which is optionallysubstituted with one or more R⁷;

X and Y are independently selected from —O— and —NR⁸—;

R⁴ and R⁵ are indepdedently selected from:

-   -   hydrogen; and    -   C₁₋₆ alkyl and phenyl, each of which is independently optionally        substituted at each occurrence with one or more substituents        selected from halogen, —NO₂, —CN, —OR, —SR, —N(R⁸)₂, —NR⁹R¹⁰,        —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,        —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —S—S—R⁸, —S—C(O)R⁸, —C(O)R⁸,        —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰,        —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰,        —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂, —P(O)(R⁸)₂, —OP(O)(OR⁸)₂,        ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to 12-membered        heterocycle;

R⁶ is selected from hydrogen, halogen and cyano; and C₁₋₆ alkyl,optionally substituted with one or more R⁷;

R⁷ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸,        —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,        —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,        —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,        —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰,        —P(O)(OR⁸)₂, —P(O)(R⁸)₂, ═O, ═S, and ═N(R⁸);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁸,        —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to        12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁷ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁸, —SR⁸,        —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl;

R⁸ is independently selected at each occurrence from hydrogen; and C₁₋₂₀alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle; and

R⁹ and R¹⁰ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁷.

In some embodiments, for a compound of Formula (I), (II) or (III), R¹and R² are taken together with the nitrogen atom to which they areattached to form a 3- to 12-membered heterocycle, optionally substitutedwith one or more R⁷. In some embodiments, R¹ and R² are taken togetherwith the nitrogen atom to which they are attached to form a 3- to12-membered heterocycle, optionally substituted with one or moresubstituents independently selected from halogen, —CN, C₁₋₄ alkyl, C₁₋₃haloalkyl, —OH and —NH₂. In some embodiments, R¹ and R² are takentogether with the nitrogen atom to which they are attached to formoptionally substituted 3- to 7-membered monocyclic heterocycloalkyl oroptionally substituted 5- to 12-membered fused bicyclicheterocycloalkyl.

In some embodiments, for a compound of Formula (I), (II) or (III), R² isselected from C₁₋₆ alkyl, C₃₋₁₂ carbocycle, 3- to 12-memberedheterocycle and benzyl, each of which is optionally substituted with oneor more substituents independently selected from halogen, —CN, C₁₋₄alkyl, C₁₋₃ haloalkyl, —OH and —NH₂. In some embodiments, R² is benzyl,optionally substituted with one or more R⁷. In some embodiments, R² isbenzyl, optionally substituted with one or more substituentsindependently selected from halogen, —CN, C₁₋₄ alkyl, C₁₋₃ haloalkyl,—OH and —NH₂.

In certain aspects, the present disclosure provides a compound ofFormula (III-A) or (III-B):

or a pharmaceutically acceptable salt thereof, wherein:

W¹ is selected from N, NR⁸, CR⁶, and S;

W² and W³ are each independently selected from N and CR⁶;

W⁴ and W⁵ are each independently selected from N and C;

W⁶ is selected from N, CR⁶, and S;

-   -   wherein at least one of W¹, W², W³, W⁴, W⁵, and W⁶ is N, and        provided that:        -   when W¹, W², W³, W⁵, and W⁶ are N, W⁴ is not N; and        -   when either W¹ or W⁶ is S, the other is CR⁶;    -   R¹ is selected from hydrogen; and C₁₋₆ alkyl and C₃₋₁₂        carbocycle, each of which is optionally substituted with one or        more R⁷;    -   R³ is selected from hydrogen, halogen, cyano, —N(R⁸)₂ and —OR⁸;        and C₁₋₆ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle,        3- to 12-membered heterocycle and benzyl, each of which is        optionally substituted with one or more R⁷;

A is selected from —O—, —S—, —S(═O)— and —S(═O)₂—;

X and Y are independently selected from —O— and —NR⁸—;

R⁴ and R⁵ are independently selected from:

-   -   hydrogen; and    -   C₁₋₆ alkyl, phenyl, and 3- to 12-membered heterocycle, each of        which is independently optionally substituted at each occurrence        with one or more substituents selected from halogen, —NO₂, —CN,        —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸,        —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂,        —NR⁸S(═O)₂NR⁹R¹⁰, —S—S—R⁸, —S—C(O)R⁸, —C(O)R⁸, —C(O)OR⁸,        —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸,        —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂,        —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂, —P(O)(R⁸)₂, —OP(O)(OR⁸)₂, ═O, ═S,        ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle; or

R⁴ and R⁵ are taken together with the atoms to which they are attachedto form a 3- to 12-membered heterocycle, optionally substituted with oneor more R⁷;

R⁶ is selected from hydrogen, halogen and cyano; and C₁₋₆ alkyl,optionally substituted with one or more R⁷;

R⁷ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸,        —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,        —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,        —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,        —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰,        —P(O)(OR⁸)₂, —P(O)(R⁸)₂, ═O, ═S, and ═N(R⁸);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁸,        —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to        12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁷ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁸, —SR⁸,        —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl;

R⁸ is independently selected at each occurrence from hydrogen; and C₁₋₂₀alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁹ and R¹⁰ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁷;

R¹³ is selected from hydrogen and C₁₋₆ alkyl;

R¹⁴ is selected from hydrogen and R⁷;

R¹¹ is selected from C₁₋₆ alkyl and C₃₋₁₂ carbocycle, each of which isoptionally substituted with one or more R⁷;

R¹² is independently selected at each occurrence from R⁷; and

n is an integer from 0 to 3.

In certain aspects, the present disclosure provides a compound ofFormula (II-A) or (II-B):

or a pharmaceutically acceptable salt thereof, wherein:

W¹, W² and W³ are each independently selected from N and CR⁶, wherein atleast one of W¹, W² and W³ is N;

R¹ is selected from hydrogen; and C₁₋₆ alkyl and C₃₋₁₂ carbocycle, eachof which is optionally substituted with one or more R⁷;

R³ is selected from hydrogen, halogen and cyano; and C₁₋₆ alkyl, C₃₋₁₂carbocycle, 3- to 12-membered heterocycle and benzyl, each of which isoptionally substituted with one or more R⁷;

A is selected from —S—, —S(═O)— and —S(═O)₂—;

X and Y are independently selected from —O— and —NR⁸—;

R⁴ and R⁵ are independently selected from:

-   -   hydrogen; and    -   C₁₋₆ alkyl and phenyl, each of which is independently optionally        substituted at each occurrence with one or more substituents        selected from halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰,        —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,        —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —S—S—R⁸, —S—C(O)R⁸, —C(O)R⁸,        —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰,        —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰,        —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂, —P(O)(R⁸)₂, —OP(O)(OR⁸)₂,        ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to 12-membered        heterocycle;

R⁶ is selected from hydrogen, halogen and cyano; and C₁₋₆ alkyl,optionally substituted with one or more R⁷;

R⁷ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸,        —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,        —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,        —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,        —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰,        —P(O)(OR⁸)₂, —P(O)(R⁸)₂, ═O, ═S, and ═N(R⁸);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁸,        —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to        12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁷ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁸, —SR⁸,        —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl;

R⁸ is independently selected at each occurrence from hydrogen; and C₁₋₂₀alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁹ and R¹⁰ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁷;

R¹¹ is selected from C₁₋₆ alkyl and C₃₋₁₂ carbocycle, each of which isoptionally substituted with one or more R⁷;

R¹² is independently selected at each occurrence from R⁷; and

n is an integer from 0 to 3.

In certain aspects, the present disclosure provides a compound ofFormula (I-A) or (I-B):

or a pharmaceutically acceptable salt thereof, wherein:

W¹, W² and W³ are each independently selected from N and CR⁶, wherein atleast one of W¹, W² and W³ is N;

R¹ is selected from hydrogen; and C₁₋₆ alkyl and C₃₋₁₂ carbocycle, eachof which is optionally substituted with one or more R⁷;

R³ is selected from halogen and cyano; and C₁₋₆ alkyl, C₃₋₁₂ carbocycle,3- to 12-membered heterocycle and benzyl, each of which is optionallysubstituted with one or more R⁷;

X andY are independently selected from —O— and —NR⁸—;

R⁴ and R⁵ are independently selected from:

-   -   hydrogen; and    -   C₁₋₆ alkyl and phenyl, each of which is independently optionally        substituted at each occurrence with one or more substituents        selected from halogen, —NO₂, —CN, —OR, —SR, —N(R⁸)₂, —NR⁹R¹⁰,        —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,        —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —S—S—R⁸, —S—C(O)R⁸, —C(O)R⁸,        —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰,        —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰,        —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂, —P(O)(R⁸)₂, —OP(O)(OR⁸)₂,        ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to 12-membered        heterocycle;

R⁶ is selected from hydrogen, halogen and cyano; and C₁₋₆ alkyl,optionally substituted with one or more R⁷;

R⁷ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸,        —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,        —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,        —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,        —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰,        —P(O)(OR⁸)₂, —P(O)(R⁸)₂, ═O, ═S, and ═N(R⁸);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁸,        —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to        12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁷ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁸, —SR⁸,        —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl;

R⁸ is independently selected at each occurrence from hydrogen; and C₁₋₂₀alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁹ and R¹⁰ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁷;

R¹¹ is selected from C₁₋₆ alkyl and C₃₋₁₂ carbocycle, each of which isoptionally substituted with one or more R⁷;

R¹² is independently selected at each occurrence from R⁷; and

n is an integer from 0 to 3.

In some embodiments, for a compound of Formula (I-A), (I-B), (II-A),(II-B), (III-A) or (III-B), R¹¹ is C₁₋₄ alkyl. In some embodiments, R¹¹is selected from methyl, ethyl, iso-propyl and tert-butyl. In someembodiments, R¹¹ is selected from C₁₋₄ alkyl and C₃₋₁₂ cycloalkyl, eachof which is optionally substituted with one or more R⁷. In someembodiments, R¹² is independently selected at each occurrence fromhalogen, —CN, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkyl and C₁₋₄haloalkyl. In some embodiments, R¹² is independently selected at eachoccurrence from halogen, —CN, C₁₋₄ alkyl and C₁₋₄ haloalkyl. In someembodiments, R¹² is independently selected at each occurrence from F,—CN, —CH₃ and —CF₃. In some embodiments, n is an integer from 1 to 3.

In certain aspects, the present disclosure provides a compound ofFormula (III-C):

or a pharmaceutically acceptable salt thereof, wherein:

W¹ is selected from N, NR⁸, CR⁶, and S;

W² and W³ are each independently selected from N and CR⁶;

W⁴ and W⁵ are each independently selected from N and C;

W⁶ is selected from N, CR⁶, and S;

-   -   wherein at least one of W¹, W², W³, W⁴, W⁵, and W⁶ is N, and        provided that:        -   when W¹, W², W³, W⁵, and W⁶ are N, W⁴ is not N; and        -   when either W¹ or W⁶ is S, the other is CR⁶;

R¹ is selected from hydrogen; and C₁₋₆ alkyl and C₃₋₁₂ carbocycle, eachof which is optionally substituted with one or more R⁷;

R³ is selected from hydrogen, halogen, cyano, —N(R⁸)₂ and —OR⁸; and C₁₋₆alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, 3- to 12-memberedheterocycle and benzyl, each of which is optionally substituted with oneor more R⁷;

A is selected from —O—, —S—, —S(═O)— and —S(═O)₂—;

X and Y are independently selected from —O— and —NR⁸—;

R⁴ and R⁵ are independently selected from:

-   -   hydrogen; and    -   C₁₋₆ alkyl, phenyl, and 3- to 12-membered heterocycle, each of        which is independently optionally substituted at each occurrence        with one or more substituents selected from halogen, —NO₂, —CN,        —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸,        —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂,        —NR⁸S(═O)₂NR⁹R¹⁰, —S—S—R⁸, —S—C(O)R⁸, —C(O)R⁸, —C(O)OR⁸,        —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸,        —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂,        —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂, —P(O)(R⁸)₂, —OP(O)(OR⁸)₂, ═O, ═S,        ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle; or

R⁴ and R⁵ are taken together with the atoms to which they are attachedto form a 3- to 12-membered heterocycle, optionally substituted with oneor more R⁷;

R⁶ is selected from hydrogen, halogen and cyano; and C₁₋₆ alkyl,optionally substituted with one or more R⁷;

R⁷ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸,        —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,        —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,        —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,        —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰,        —P(O)(OR⁸)₂, —P(O)(R⁸)₂, ═O, ═S, and ═N(R⁸);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁸,        —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to        12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁷ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁸, —SR⁸,        —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl;

R⁸ is independently selected at each occurrence from hydrogen; and C₁₋₂₀alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁹ and R¹⁰ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁷;

R¹³ is selected from hydrogen and C₁₋₆ alkyl;

R¹⁴ is selected from hydrogen and R⁷; and

Z is selected from C₃₋₁₂ cycloalkyl and 3- to 12-memberedheterocycloalkyl, each of which is optionally substituted with one ormore R⁷.

In certain aspects, the present disclosure provides a compound ofFormula (II-C):

or a pharmaceutically acceptable salt thereof, wherein:

W¹, W² and W³ are each independently selected from N and CR⁶, wherein atleast one of W¹, W² and W³ is N;

R¹ is selected from hydrogen; and C₁₋₆ alkyl and C₃₋₁₂ carbocycle, eachof which is optionally substituted with one or more R⁷;

R³ is selected from hydrogen, halogen and cyano; and C₁₋₆ alkyl, C₃₋₁₂carbocycle, 3- to 12-membered heterocycle and benzyl, each of which isoptionally substituted with one or more R⁷;

A is selected from —S—, —S(═O)— and —S(═O)₂—;

X and Y are independently selected from —O— and —NR⁸—;

R⁴ and R⁵ are independently selected from:

-   -   hydrogen; and    -   C₁₋₆ alkyl and phenyl, each of which is independently optionally        substituted at each occurrence with one or more substituents        selected from halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰,        —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,        —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —S—S—R⁸, —S—C(O)R⁸, —C(O)R⁸,        —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰,        —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰,        —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂, —P(O)(R⁸)₂, —OP(O)(OR⁸)₂,        ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to 12-membered        heterocycle;

R⁶ is selected from hydrogen, halogen and cyano; and C₁₋₆ alkyl,optionally substituted with one or more R⁷;

R⁷ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸,        —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,        —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,        —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,        —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰,        —P(O)(OR⁸)₂, —P(O)(R⁸)₂, ═O, ═S, and ═N(R⁸);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁸,        —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to        12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁷ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁸, —SR⁸,        —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl;

R⁸ is independently selected at each occurrence from hydrogen; and C₁₋₂₀alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁹ and R¹⁰ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁷; and

Z is selected from C₃₋₁₂ cycloalkyl and 3- to 12-memberedheterocycloalkyl, each of which is optionally substituted with one ormore R⁷.

In certain aspects, the present disclosure provides a compound ofFormula (I-C):

or a pharmaceutically acceptable salt thereof, wherein:

W¹, W² and W³ are each independently selected from N and CR⁶, wherein atleast one of W¹, W² and W³ is N;

R¹ is selected from hydrogen; and C₁₋₆ alkyl and C₃₋₁₂ carbocycle, eachof which is optionally substituted with one or more R⁷;

R³ is selected from halogen and cyano; and C₁₋₆ alkyl, C₃₋₁₂ carbocycle,3- to 12-membered heterocycle and benzyl, each of which is optionallysubstituted with one or more R⁷;

X and Y are independently selected from —O— and —NR⁸—;

R⁴ and R⁵ are independently selected from:

-   -   hydrogen; and    -   C₁₋₆ alkyl and phenyl, each of which is independently optionally        substituted at each occurrence with one or more substituents        selected from halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰,        —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,        —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —S—S—R⁸, —S—C(O)R⁸, —C(O)R⁸,        —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰,        —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰,        —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂, —P(O)(R⁸)₂, —OP(O)(OR⁸)₂,        ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to 12-membered        heterocycle;

R⁶ is selected from hydrogen, halogen and cyano; and C₁₋₆ alkyl,optionally substituted with one or more R⁷;

R⁷ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸,        —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,        —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,        —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,        —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰,        —P(O)(OR⁸)₂, —P(O)(R⁸)₂, ═O, ═S, and ═N(R⁸);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁸,        —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to        12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁷ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁸, —SR⁸,        —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl;

R⁸ is independently selected at each occurrence from hydrogen; and C₁₋₂₀alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁹ and R¹⁰ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁷; and

Z is selected from C₃₋₁₂ cycloalkyl and 3- to 12-memberedheterocycloalkyl, each of which is optionally substituted with one ormore R⁷.

In some embodiments, for a compound of Formula (I-C), (II-C) or (III-C),Z is selected from C₃₋₁₂ monocyclic cycloalkyl or C₅₋₁₂ fused bicycliccycloalkyl, each of which is optionally substituted with one or more R⁷.In some embodiments, Z is C₅₋₁₂ fused bicyclic cycloalkyl, optionallysubstituted with one or more R⁷. In some embodiments, Z is substitutedwith one or more substituents independently selected from halogen, —CN,C₁₋₄ alkyl and C₁₋₃ haloalkyl.

In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-C),(II), (II-A), (II-B), (II-C), (III), (III-A), (III-B) or (III-C), R¹ isselected from hydrogen and —CH₃.

In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-C),(II), (II-A), (II-B), (II-C), (III), (III-A), (III-B) or (III-C), W³ isN. In some embodiments, W² is N or CH. In some embodiments, W² is N. Insome embodiments, W¹ is N or CH. In some embodiments, W¹ is N. In someembodiments, W¹ is N or CH, W² is N and W³ is N.

In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-C),(II), (II-A), (II-B), (II-C), (III), (III-A), (III-B) or (III-C), R³ isselected from halogen and cyano; and C₁₋₆ alkyl, C₃₋₁₂ carbocycle, 3- to12-membered heterocycle and benzyl, each of which is optionallysubstituted with one or more R⁷. In some embodiments, R³ is selectedfrom hydrogen, halogen, —CN, C₁₋₃ alkyl and C₁₋₃ haloalkyl. In someembodiments, R³ is selected from halogen, —CN, C₁₋₃ alkyl and C₁₋₃haloalkyl. In some embodiments, R³ is selected from —Cl and —CN.

In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-C),(II), (II-A), (II-B), (II-C), (III), (III-A), (III-B) or (III-C), atleast one of R⁴ and R⁵ is C₁₋₆ alkyl, optionally substituted at eachoccurrence with one or more substituents selected from halogen, —OR,—S—S—R⁸, —S—C(O)R⁸, —OC(O)R⁸, —OC(O)OR⁸ and —P(O)(OR⁸)₂. In someembodiments, R⁴ and R⁵ are independently selected from C₁₋₆ alkyl,optionally substituted at each occurrence with one or more substituentsselected from halogen, —OR⁸, —S—S—R⁸, —S—C(O)R⁸, —OC(O)R⁸, —OC(O)OR⁸ and—P(O)(OR⁸)₂. In some embodiments, R⁴ and R⁵ are independently selectedfrom hydrogen and C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, —OR⁸, —S—S—R⁸, —S—C(O)R⁸, —OC(O)R⁸, —OC(O)OR⁸ and—P(O)(OR⁸)₂. In some embodiments, R⁴ and R⁵ are independently selectedfrom —CH₂OC(O)R⁸ and —CH₂OC(O)OR⁸. In some embodiments, R⁴ and R⁵ areindependently selected from —CH₂OC(O)C(CH₃)₃, —CH₂OC(O)OCH(CH₃)₂,—CH₂OC(O)CH₃, —CH₂CH₂—S—S—(CH₂)₂OH and —CH₂CH₂—S—C(O)CH₃. In someembodiments, R⁴ is phenyl, optionally substituted with —OR; R⁵ is C₁₋₆alkyl substituted with one or more substituents selected from —OC(O)R⁸,—C(O)OR⁸, and —OC(O)OR⁸; and R⁸ is C₁₋₆ alkyl.

In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-C),(II), (II-A), (II-B), (II-C), (III), (III-A), (III-B) or (III-C), X andY are each —O—. In some embodiments, one of X and Y is —O— and the otherone of X and Y is —NR⁸—. In some embodiments, —X—R⁴ and —Y—R⁵ are each—OH.

In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-C),(II), (II-A), (II-B), (II-C), (III), (III-A), (III-B) or (III-C), W¹ isselected from N and CR⁶; W² is selected from N and CH; W³ is N; R¹ isselected from hydrogen and C₁₋₄ alkyl; R³ is selected from halogen andcyano; and R⁶ is selected from hydrogen, halogen, cyano and C₁₋₄ alkyl.In some embodiments, W¹ is selected from N and CR⁶; W² is selected fromN and CH; W³ is N; R¹ is selected from hydrogen and C₁₋₄ alkyl; R³ isselected from halogen and cyano; and R⁶ is selected from halogen, cyanoand C₁₋₄ alkyl.

In some embodiments, for a compound of Formula (III), (III-A), (III-B)or (III-C), R³ is selected from optionally substituted C₂-alkynyl and—OR⁸. In some embodiments, R³ is selected from

In some embodiments, for a compound of Formula (III), (III-A), (III-B)or (III-C), W¹ is selected from N and CR⁶; W² is selected from N and CH;W³ is N; W⁴ is C; W⁵ is N; W⁶ is CH; R¹ is selected from hydrogen andC₁₋₄ alkyl; R³ is selected from halogen and cyano; and R⁶ is selectedfrom hydrogen, halogen, cyano and C₁₋₄ alkyl. In some embodiments, W¹ isCH; W² is N; W³ is N; W⁴ is C; W⁵ is N; W⁶ is CH; R¹ is selected fromhydrogen; R² is C₃₋₁₂ carbocycle; and R³ is selected from optionallysubstituted C₂-alkynyl and —OR⁸.

In certain aspects, the present disclosure provides a substantially purestereoisomer of a compound of Formula (I), (I-A), (I-B), (I-C), (II),(II-A), (II-B), (II-C), (III), (III-A), (III-B) or (III-C). In someembodiments, the stereoisomer is provided in at least 90% diastereomericexcess.

In certain aspects, the present disclosure provides a compound selectedfrom Table 1.

In certain aspects, the present disclosure provides a pharmaceuticalcomposition comprising a compound or salt described herein, such as acompound of Formula (I), (I-A), (I-B), (I-C), (II), (II-A), (II-B),(II-C), (III), (III-A), (III-B) or (III-C), and a pharmaceuticallyacceptable carrier or diluent.

In certain aspects, the present disclosure provides a method ofinhibiting CD73-catalyzed hydrolysis of adenosine monophosphate,comprising contacting CD73 with an effective amount of a compounddescribed herein, such as a compound of Formula (I), (I-A), (I-B),(I-C), (II), (II-A), (II-B), (II-C), (III), (III-A), (III-B) or (III-C).The contacting may comprise contacting a cell that expresses CD73. Thecontacting may take place in vivo.

INCORPORATION BY REFERENCE

All publications, patents and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes and substitutions will now occur to those skilled inthe art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe appended claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs.

As used in the specification and claims, the singular form “a”, “an” and“the” include plural references unless the context clearly dictatesotherwise.

The term “C_(x-y)” or “C_(x)-C_(y)” when used in conjunction with achemical moiety, such as alkyl, alkenyl, or alkynyl is meant to includegroups that contain from x to y carbons in the chain. For example, theterm “C_(x-y) alkyl” refers to substituted or unsubstituted saturatedhydrocarbon groups, including straight-chain alkyl and branched-chainalkyl groups that contain from x to y carbons in the chain.

“Alkyl” refers to substituted or unsubstituted saturated hydrocarbongroups, including straight-chain alkyl and branched-chain alkyl groups.An alkyl group may contain from one to twelve carbon atoms (e.g., C₁₋₁₂alkyl), such as one to eight carbon atoms (C₁₋₈ alkyl) or one to sixcarbon atoms (C₁₋₆ alkyl). Exemplary alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl. An alkylgroup is attached to the rest of the molecule by a single bond. Unlessstated otherwise specifically in the specification, an alkyl group isoptionally substituted by one or more substituents such as thosesubstituents described herein.

“Haloalkyl” refers to an alkyl group that is substituted by one or morehalogens. Exemplary haloalkyl groups include trifluoromethyl,difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

“Alkenyl” refers to substituted or unsubstituted hydrocarbon groups,including straight-chain or branched-chain alkenyl groups containing atleast one double bond. An alkenyl group may contain from two to twelvecarbon atoms (e.g., C₂₋₁₂ alkenyl). Exemplary alkenyl groups includeethenyl (i.e., vinyl), prop-1-enyl, but-1-enyl, pent-1-enyl,penta-1,4-dienyl, and the like. Unless stated otherwise specifically inthe specification, an alkenyl group is optionally substituted by one ormore substituents such as those substituents described herein.

“Alkynyl” refers to substituted or unsubstituted hydrocarbon groups,including straight-chain or branched-chain alkynyl groups containing atleast one triple bond. An alkynyl group may contain from two to twelvecarbon atoms (e.g., C₂₋₁₂ alkynyl). Exemplary alkynyl groups includeethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unlessstated otherwise specifically in the specification, an alkynyl group isoptionally substituted by one or more substituents such as thosesubstituents described herein.

“Alkylene” or “alkylene chain” refers to substituted or unsubstituteddivalent saturated hydrocarbon groups, including straight-chain alkyleneand branched-chain alkylene groups that contain from one to twelvecarbon atoms. Exemplary alkylene groups include methylene, ethylene,propylene, and n-butylene. Similarly, “alkenylene” and “alkynylene”refer to alkylene groups, as defined above, which comprise one or morecarbon-carbon double or triple bonds, respectively. The points ofattachment of the alkylene, alkenylene or alkynylene chain to the restof the molecule can be through one carbon or any two carbons within thechain. Unless stated otherwise specifically in the specification, analkylene, alkenylene, or alkynylene group is optionally substituted byone or more substituents such as those substituents described herein.

“Heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” refer to substitutedor unsubstituted alkyl, alkenyl and alkynyl groups which respectivelyhave one or more skeletal chain atoms selected from an atom other thancarbon, e.g., O, N, P, Si, S or combinations thereof, and wherein thenitrogen, phosphorus, and sulfur atoms may optionally be oxidized andthe nitrogen heteroatom may optionally be quaternized. If given, anumerical range refers to the chain length in total. For example, a 3-to 8-membered heteroalkyl has a chain length of 3 to 8 atoms. Connectionto the rest of the molecule may be through either a heteroatom or acarbon in the heteroalkyl, heteroalkenyl or heteroalkynyl chain. Unlessstated otherwise specifically in the specification, a heteroalkyl,heteroalkenyl, or heteroalkynyl group is optionally substituted by oneor more substituents such as those substituents described herein.

“Heteroalkylene”, “heteroalkenylene” and “heteroalkynylene” refer tosubstituted or unsubstituted alkylene, alkenylene and alkynylene groupswhich respectively have one or more skeletal chain atoms selected froman atom other than carbon, e.g., O, N, P, Si, S or combinations thereof,and wherein the nitrogen, phosphorus, and sulfur atoms may optionally beoxidized and the nitrogen heteroatom may optionally be quaternized. Thepoints of attachment of the heteroalkylene, heteroalkenylene orheteroalkynylene chain to the rest of the molecule can be through eitherone heteroatom or one carbon, or any two heteroatoms, any two carbons,or any one heteroatom and any one carbon in the heteroalkyl,heteroalkenyl or heteroalkynyl chain. Unless stated otherwisespecifically in the specification, a heteroalkylene, heteroalkenylene,or heteroalkynylene group is optionally substituted by one or moresubstituents such as those substituents described herein.

“Carbocycle” refers to a saturated, unsaturated or aromatic ring inwhich each atom of the ring is a carbon atom. Carbocycle may include 3-to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle maybe selected from saturated, unsaturated, and aromatic rings. In someembodiments, the carbocycle is an aryl. In some embodiments, thecarbocycle is a cycloalkyl. In some embodiments, the carbocycle is acycloalkenyl. In an exemplary embodiment, an aromatic ring, e.g.,phenyl, may be fused to a saturated or unsaturated ring, e.g.,cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated,unsaturated and aromatic bicyclic rings, as valence permits, areincluded in the definition of carbocyclic. Exemplary carbocycles includecyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, andnaphthyl. Unless stated otherwise specifically in the specification, acarbocycle is optionally substituted by one or more substituents such asthose substituents described herein.

“Heterocycle” refers to a saturated, unsaturated or aromatic ringcomprising one or more heteroatoms. Exemplary heteroatoms include N, O,Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclicrings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridgedrings. Each ring of a bicyclic heterocycle may be selected fromsaturated, unsaturated, and aromatic rings. The heterocycle may beattached to the rest of the molecule through any atom of theheterocycle, valence permitting, such as a carbon or nitrogen atom ofthe heterocycle. In some embodiments, the heterocycle is a heteroaryl.In some embodiments, the heterocycle is a heterocycloalkyl. In anexemplary embodiment, a heterocycle, e.g., pyridyl, may be fused to asaturated or unsaturated ring, e.g., cyclohexane, cyclopentane, orcyclohexene. Exemplary heterocycles include pyrrolidinyl, pyrrolyl,imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl,indazolyl, indolyl, and quinolinyl. Unless stated otherwise specificallyin the specification, a heterocycle is optionally substituted by one ormore substituents such as those substituents described herein.

“Heteroaryl” refers to a 3- to 12-membered aromatic ring that comprisesat least one heteroatom wherein each heteroatom may be independentlyselected from N, O, and S. As used herein, the heteroaryl ring may beselected from monocyclic or bicyclic and fused or bridged ring systemswherein at least one of the rings in the ring system is aromatic, i.e.,it contains a cyclic, delocalized (4n+2) π-electron system in accordancewith the Hickel theory. The heteroatom(s) in the heteroaryl may beoptionally oxidized. One or more nitrogen atoms, if present, areoptionally quaternized. The heteroaryl may be attached to the rest ofthe molecule through any atom of the heteroaryl, valence permitting,such as a carbon or nitrogen atom of the heteroaryl. Examples ofheteroaryls include, but are not limited to, azepinyl, acridinyl,benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl,benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolin yl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, aheteroaryl is optionally substituted by one or more substituents such asthose substituents described herein.

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more carbons or heteroatoms of the structure. Itwill be understood that “substitution” or “substituted with” includesthe implicit proviso that such substitution is in accordance withpermitted valence of the substituted atom and the substituent, and thatthe substitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, etc. As used herein, the term “substituted” iscontemplated to include all permissible substituents of organiccompounds. In a broad aspect, the permissible substituents includeacyclic and cyclic, branched and unbranched, carbocyclic andheterocyclic, aromatic and non-aromatic substituents of organiccompounds. The permissible substituents can be one or more and the sameor different for appropriate organic compounds. For purposes of thisdisclosure, the heteroatoms such as nitrogen may have hydrogensubstituents and/or any permissible substituents of organic compoundsdescribed herein which satisfy the valences of the heteroatoms.Substituents can include any substituents described herein, for example,a halogen, a hydroxyl, a carbonyl (such as a carboxyl, analkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as athioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, aphosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine,an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, asulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, aheterocyclyl, an aralkyl, a carbocycle, a heterocycle, a cycloalkyl, aheterocycloalkyl, an aromatic and heteroaromatic moiety. In someembodiments, substituents may include any substituents described herein,for example: halogen, hydroxy, oxo (═O), thioxo (═S), cyano (—CN), nitro(—NO₂), imino (═N—H), oximo (═N—OH), hydrazino (═N—NH₂), —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2), and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2); and alkyl, alkenyl,alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl,and heteroarylalkyl any of which may be optionally substituted by alkyl,alkenyl, alkynyl, halogen, hydroxy, haloalkyl, haloalkenyl, haloalkynyl,oxo (═O), thioxo (═S), cyano (—CN), nitro (—NO₂), imino (═N—H), oximo(═N—OH), hydrazine (═N—NH₂), —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a),—R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b-)N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2);wherein each R^(a) is independently selected from hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein eachR^(a), valence permitting, may be optionally substituted with alkyl,alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo(═O), thioxo (═S), cyano (—CN), nitro (—NO₂), imino (═N—H), oximo(═N—OH), hydrazine (═N—NH₂), —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a),—R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2);and wherein each R^(b) is independently selected from a direct bond or astraight or branched alkylene, alkenylene, or alkynylene chain, and eachR^(c) is a straight or branched alkylene, alkenylene or alkynylenechain. In some embodiments, a substituent is selected from R⁷ as definedherein below.

It will be understood by those skilled in the art that substituents canthemselves be substituted, if appropriate. Unless specifically stated as“unsubstituted,” references to chemical moieties herein are understoodto include substituted variants. For example, reference to a“heteroaryl” group or moiety implicitly includes both substituted andunsubstituted variants.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where the event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl group may or may not be substituted and that the descriptionincludes both substituted aryl groups and aryl groups having nosubstitution.

Compounds of the present disclosure also include crystalline andamorphous forms of those compounds, pharmaceutically acceptable salts,and active metabolites of these compounds having the same type ofactivity, including, for example, polymorphs, pseudopolymorphs,solvates, hydrates, unsolvated polymorphs (including anhydrates),conformational polymorphs, and amorphous forms of the compounds, as wellas mixtures thereof.

The compounds described herein may exhibit their natural isotopicabundance, or one or more of the atoms may be artificially enriched in aparticular isotope having the same atomic number, but an atomic mass ormass number different from the atomic mass or mass number predominantlyfound in nature. All isotopic variations of the compounds of the presentdisclosure, whether radioactive or not, are encompassed within the scopeof the present disclosure. For example, hydrogen has three naturallyoccurring isotopes, denoted ¹H (protium), ²H (deuterium), and ³H(tritium). Protium is the most abundant isotope of hydrogen in nature.Enriching for deuterium may afford certain therapeutic advantages, suchas increased in vivo half-life and/or exposure, or may provide acompound useful for investigating in vivo routes of drug elimination andmetabolism. Isotopically-enriched compounds may be prepared byconventional techniques well known to those skilled in the art.

“Isomers” are different compounds that have the same molecular formula.“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space. “Enantiomers” are a pair of stereoisomers that arenon superimposable mirror images of each other. A 1:1 mixture of a pairof enantiomers is a “racemic” mixture. The term “(±)” is used todesignate a racemic mixture where appropriate. “Diastereoisomers” or“diastereomers” are stereoisomers that have at least two asymmetricatoms but are not mirror images of each other. The absolutestereochemistry is specified according to the Cahn-Ingold-Prelog R-Ssystem. When a compound is a pure enantiomer, the stereochemistry ateach chiral carbon can be specified by either R or S. Resolved compoundswhose absolute configuration is unknown can be designated (+) or (−)depending on the direction (dextro- or levorotatory) in which theyrotate plane polarized light at the wavelength of the sodium D line.Certain compounds described herein contain one or more asymmetriccenters and can thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms, the asymmetric centers of which can be defined, interms of absolute stereochemistry, as (R)- or (S)-. The present chemicalentities, pharmaceutical compositions and methods are meant to includeall such possible stereoisomers, including racemic mixtures, opticallypure forms, mixtures of diastereomers and intermediate mixtures.Optically active (R)- and (S)-isomers can be prepared using chiralsynthons or chiral reagents, or resolved using conventional techniques.The optical activity of a compound can be analyzed via any suitablemethod, including but not limited to chiral chromatography andpolarimetry, and the degree of predominance of one stereoisomer over theother isomer can be determined.

Chemical entities having carbon-carbon double bonds or carbon-nitrogendouble bonds may exist in Z- or E- form (or cis- or trans- form).Furthermore, some chemical entities may exist in various tautomericforms. Unless otherwise specified, chemical entities described hereinare intended to include all Z-, E- and tautomeric forms as well.

Isolation and purification of the chemical entities and intermediatesdescribed herein can be effected, if desired, by any suitable separationor purification procedure such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography orthick-layer chromatography, or a combination of these procedures.Specific illustrations of suitable separation and isolation procedurescan be had by reference to the examples herein below. However, otherequivalent separation or isolation procedures can also be used.

When stereochemistry is not specified, certain small molecules describedherein include, but are not limited to, when possible, their isomers,such as enantiomers and diastereomers, mixtures of enantiomers,including racemates, mixtures of diastereomers, and other mixturesthereof, to the extent they can be made by one of ordinary skill in theart by routine experimentation. In those situations, the singleenantiomers or diastereomers, i.e., optically active forms, can beobtained by asymmetric synthesis or by resolution of the racemates ormixtures of diastereomers. Resolution of the racemates or mixtures ofdiastereomers, if possible, can be accomplished, for example, byconventional methods such as crystallization in the presence of aresolving agent, or chromatography, using, for example, a chiralhigh-pressure liquid chromatography (HPLC) column. Furthermore, amixture of two enantiomers enriched in one of the two can be purified toprovide further optically enriched form of the major enantiomer byrecrystallization and/or trituration. In addition, such certain smallmolecules include Z- and E- forms (or cis- and trans- forms) of certainsmall molecules with carbon-carbon double bonds or carbon-nitrogendouble bonds. Where certain small molecules described herein exist invarious tautomeric forms, the term “certain small molecule” is intendedto include all tautomeric forms of the certain small molecule.

The term “salt” or “pharmaceutically acceptable salt” refers to saltsderived from a variety of organic and inorganic counter ions well knownin the art. Pharmaceutically acceptable acid addition salts can beformed with inorganic acids and organic acids. Inorganic acids fromwhich salts can be derived include, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike. Organic acids from which salts can be derived include, forexample, acetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Pharmaceutically acceptable base additionsalts can be formed with inorganic and organic bases. Inorganic basesfrom which salts can be derived include, for example, sodium, potassium,lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese,aluminum, and the like. Organic bases from which salts can be derivedinclude, for example, primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines, basic ion exchange resins, and the like, specificallysuch as isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, and ethanolamine. In some embodiments, thepharmaceutically acceptable base addition salt is chosen from ammonium,potassium, sodium, calcium, and magnesium salts.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye, colorant, flavor enhancer,surfactant, wetting agent, dispersing agent, suspending agent,stabilizer, isotonic agent, solvent, or emulsifier which has beenapproved by the United States Food and Drug Administration as beingacceptable for use in humans or domestic animals.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound described herein that is sufficient toaffect the intended application, including but not limited to diseasetreatment, as defined below. The therapeutically effective amount mayvary depending upon the intended treatment application (in vivo), or thesubject and disease condition being treated, e.g., the weight and age ofthe subject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. The term also applies to a dose that willinduce a particular response in target cells, e.g., reduction ofplatelet adhesion and/or cell migration. The specific dose will varydepending on the particular compounds chosen, the dosing regimen to befollowed, whether it is administered in combination with othercompounds, timing of administration, the tissue to which it isadministered, and the physical delivery system in which it is carried.

As used herein, “treatment” or “treating” refers to an approach forobtaining beneficial or desired results with respect to a disease,disorder, or medical condition including but not limited to atherapeutic benefit and/or a prophylactic benefit. By therapeuticbenefit is meant eradication or amelioration of the underlying disorderbeing treated. Also, a therapeutic benefit is achieved with theeradication or amelioration of one or more of the physiological symptomsassociated with the underlying disorder such that an improvement isobserved in the subject, notwithstanding that the subject may still beafflicted with the underlying disorder. In certain embodiments, forprophylactic benefit, the compositions are administered to a subject atrisk of developing a particular disease, or to a subject reporting oneor more of the physiological symptoms of a disease, even though adiagnosis of this disease may not have been made.

A “therapeutic effect,” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit as described above. Aprophylactic effect includes delaying or eliminating the appearance of adisease or condition, delaying or eliminating the onset of symptoms of adisease or condition, slowing, halting, or reversing the progression ofa disease or condition, or any combination thereof.

The term “co-administration,” “administered in combination with,” andtheir grammatical equivalents, as used herein, encompass administrationof two or more agents to an animal, including humans, so that bothagents and/or their metabolites are present in the subject at the sametime. Co-administration includes simultaneous administration in separatecompositions, administration at different times in separatecompositions, or administration in a composition in which both agentsare present.

The terms “antagonist” and “inhibitor” are used interchangeably, andthey refer to a compound having the ability to inhibit a biologicalfunction (e.g., activity, expression, binding, protein-proteininteraction) of a target protein or enzyme (e.g., CD73). Accordingly,the terms “antagonist” and “inhibitor” are defined in the context of thebiological role of the target protein. While preferred antagonistsherein specifically interact with (e.g., bind to) the target, compoundsthat inhibit a biological activity of the target protein by interactingwith other members of the signal transduction pathway of which thetarget protein is a member are also specifically included within thisdefinition. A preferred biological activity inhibited by an antagonistis associated with the development, growth, or spread of a tumor.

The term “agonist” as used herein refers to a compound having theability to initiate or enhance a biological function of a targetprotein, whether by inhibiting the activity or expression of the targetprotein. Accordingly, the term “agonist” is defined in the context ofthe biological role of the target polypeptide. While preferred agonistsherein specifically interact with (e.g., bind to) the target, compoundsthat initiate or enhance a biological activity of the target polypeptideby interacting with other members of the signal transduction pathway ofwhich the target polypeptide is a member are also specifically includedwithin this definition.

“Signal transduction” is a process during which stimulatory orinhibitory signals are transmitted into and within a cell to elicit anintracellular response. A modulator of a signal transduction pathwayrefers to a compound which modulates the activity of one or morecellular proteins mapped to the same specific signal transductionpathway. A modulator may augment (agonist) or suppress (antagonist) theactivity of a signaling molecule.

An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent”refers to any agent useful in the treatment of a neoplastic condition.One class of anti-cancer agents comprises chemotherapeutic agents.“Chemotherapy” means the administration of one or more chemotherapeuticdrugs and/or other agents to a cancer patient by various methods,including intravenous, oral, intramuscular, intraperitoneal,intravesical, subcutaneous, transdermal, buccal, or inhalation or in theform of a suppository.

The term “cell proliferation” refers to a phenomenon by which the cellnumber has changed as a result of division. This term also encompassescell growth by which the cell morphology has changed (e.g., increased insize) consistent with a proliferative signal.

The term “selective inhibition” or “selectively inhibit” refers to theability of a biologically active agent to preferentially reduce thetarget signaling activity as compared to off-target signaling activity,via direct or indirect interaction with the target.

“Subject” refers to an animal, such as a mammal, for example a human.The methods described herein can be useful in both human therapeuticsand veterinary applications. In some embodiments, the subject is amammal, and in some embodiments, the subject is human. “Mammal” includeshumans and both domestic animals such as laboratory animals andhousehold pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses,rabbits), and non-domestic animals such as wildlife and the like.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein (e.g., compound of Formula (I), (I-A), (I-B),(I-C), (II), (II-A), (II-B), (II-C), (III), (III-A), (III-B) or(III-C)). Thus, the term “prodrug” refers to a precursor of abiologically active compound that is pharmaceutically acceptable. Insome aspects, a prodrug is inactive when administered to a subject butis converted in vivo to an active compound, for example, by hydrolysis.In some aspects, a prodrug has reduced activity compared to that of theparent compound. The prodrug compound often offers advantages of oralbioavailability, solubility, tissue compatibility or delayed release ina mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs(1985), pp. 7-9, 21-24 (Elsevier, Amsterdam); Higuchi, T., et al.,“Pro-drugs as Novel Delivery Systems,” (1987) A.C.S. Symposium Series,Vol. 14; and Bioreversible Carriers in Drug Design, ed. Edward B. Roche,American Pharmaceutical Association and Pergamon Press) each of which isincorporated in full by reference herein. The term “prodrug” is alsomeant to include any covalently bonded carriers, which release theactive compound in vivo when such prodrug is administered to a mammaliansubject. Prodrugs of an active compound, as described herein, aretypically prepared by modifying functional groups present in the activecompound in such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent active compound. Prodrugsinclude compounds wherein a hydroxy, amino or mercapto group is bondedto any group that, when the prodrug of the active compound isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino or free mercapto group, respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of a hydroxy functional group, or acetamide, formamide andbenzamide derivatives of an amine functional group in the activecompound and the like.

The term “in vivo” refers to an event that takes place in a subject'sbody.

The term “in vitro” refers to an event that takes places outside of asubject's body. For example, an in vitro assay encompasses any assay runoutside of a subject. In vitro assays encompass cell-based assays inwhich cells alive or dead are employed. In vitro assays also encompass acell-free assay in which no intact cells are employed.

The disclosure is also meant to encompass the in vivo metabolic productsof the disclosed compounds. Such products may result from, for example,the oxidation, reduction, hydrolysis, amidation, esterification, and thelike of the administered compound, primarily due to enzymatic processes.Accordingly, the disclosure includes compounds produced by a processcomprising administering a compound of this disclosure to a mammal for aperiod of time sufficient to yield a metabolic product thereof. Suchproducts are typically identified by administering a radiolabeledcompound of the disclosure in a detectable dose to an animal, such asrat, mouse, guinea pig, monkey, or to human, allowing sufficient timefor metabolism to occur, and isolating its conversion products from theurine, blood or other biological samples.

The chemical naming protocol and structure diagrams used herein are amodified form of the I.U.P.A.C. nomenclature system, using ChemDrawProfessional 15.1 or OpenEye Scientific Software's mol2nam application.For complex chemical names employed herein, a substituent group istypically named before the group to which it attaches. For example,cyclopropylethyl comprises an ethyl backbone with a cyclopropylsubstituent. Except as described below, all bonds are identified in thechemical structure diagrams herein, except for all bonds on some carbonatoms, which are assumed to be bonded to sufficient hydrogen atoms tocomplete the valency.

The present disclosure provides compounds that are capable ofselectively binding to and/or modulating CD73. In some embodiments, thecompounds modulate CD73 by binding to or interacting with one or moreamino acids. The binding of these compounds may disrupt the ability ofCD73 to hydrolyze adenosine monophosphate (AMP).

In certain aspects, the present disclosure provides a compound ofFormula (I):

or a pharmaceutically acceptable salt thereof, wherein:

W¹, W² and W³ are each independently selected from N and CR⁶, wherein atleast one of W¹, W² and W³ is N;

R¹ is selected from hydrogen; and C₁₋₆ alkyl and C₃₋₁₂ carbocycle, eachof which is optionally substituted with one or more R⁷;

R² is selected from C₁₋₆ alkyl, C₃₋₁₂ carbocycle, 3- to 12-memberedheterocycle and benzyl, each of which is optionally substituted with oneor more R⁷; or

R¹ and R² are taken together with the nitrogen atom to which they areattached to form a 3- to 12-membered heterocycle, optionally substitutedwith one or more R⁷;

R³ is selected from halogen and cyano; and C₁₋₆ alkyl, C₃₋₁₂ carbocycle,3- to 12-membered heterocycle and benzyl, each of which is optionallysubstituted with one or more R⁷;

X and Y are independently selected from —O— and —NR⁸—;

R⁴ and R⁵ are independently selected from:

-   -   hydrogen; and    -   C₁₋₆ alkyl and phenyl, each of which is independently optionally        substituted at each occurrence with one or more substituents        selected from halogen, —NO₂, —CN, —OR, —SR, —N(R⁸)₂, —NR⁹R¹⁰,        —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,        —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —S—S—R⁸, —S—C(O)R⁸, —C(O)R⁸,        —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰,        —NR⁸C(O)R⁸, —NR PC(O)OR⁸, —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰,        —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂, —P(O)(R⁸)₂, —OP(O)(OR⁸)₂,        ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to 12-membered        heterocycle;

R⁶ is selected from hydrogen, halogen and cyano; and C₁₋₆ alkyl,optionally substituted with one or more R⁷;

R⁷ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸,        —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,        —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,        —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,        —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰,        —P(O)(OR⁸)₂, —P(O)(R⁸)₂, ═O, ═S, and ═N(R⁸);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁸,        —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to        12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁷ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁸, —SR⁸,        —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl;

R⁸ is independently selected at each occurrence from hydrogen; and C₁₋₂₀alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle; and

R⁹ and R¹⁰ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁷.

In some embodiments, for a compound of Formula (I), R¹ is selected fromhydrogen and C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionallysubstituted with one or more R⁷. In some embodiments, R¹ is selectedfrom hydrogen and —CH₃.

In some embodiments, for a compound of Formula (I), R² is selected fromC₁₋₆ alkyl, C₃₋₁₂ carbocycle, 3- to 12-membered heterocycle and benzyl,each of which is optionally substituted with one or more substituentsindependently selected from halogen, —CN, C₁₋₄ alkyl, C₁₋₃ haloalkyl,—OH and —NH₂. In some embodiments, R² is benzyl, optionally substitutedwith one or more R⁷. In some embodiments, R² is benzyl, optionallysubstituted with one or more substituents independently selected fromhalogen, —CN, C₁₋₄ alkyl, C₁₋₃ haloalkyl, —OH and —NH₂. In someembodiments, R² is C₁₋₆ alkyl or C₃₋₈ cycloalkyl, each of which isoptionally substituted with one or more substituents independentlyselected from halogen, —CN, C₁₋₃ haloalkyl, —OH, —NH₂, optionallysubstituted phenyl and optionally substituted pyridyl. In someembodiments, R² is C₃₋₈ cycloalkyl, such as cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl. In some embodiments, R² is C₁₋₄ alkyl, suchas methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl ortert-butyl. In some embodiments, R² is C₁₋₆ alkyl, C₃₋₈ cycloalkyl, orbenzyl, each of which is optionally substituted with one or moresubstituents independently selected from halogen, —CN, C₁₋₄ alkyl, C₁₋₃haloalkyl, —OH and —NH₂.

In some embodiments, for a compound of Formula (I), R¹ and R² are takentogether with the nitrogen atom to which they are attached to form a 3-to 12-membered heterocycle, optionally substituted with one or more R⁷,such as one or more substituents independently selected from halogen,—CN, C₁₋₄ alkyl, C₁₋₃ haloalkyl, —OH and —NH₂. In some embodiments, R¹and R² are taken together with the nitrogen atom to which they areattached to form an optionally substituted 3- to 7-membered monocyclicheterocycloalkyl or an optionally substituted 5- to 12-membered fusedbicyclic heterocycloalkyl. The 3- to 12-membered heterocycle formed byR¹, R² and the nitrogen atom to which they are attached may be selectedfrom

In some embodiments, a compound of Formula (I) is represented by Formula(I-A) or (I-B):

or a pharmaceutically acceptable salt thereof, wherein:

R¹¹ is selected from C₁₋₆ alkyl and C₃₋₁₂ carbocycle, each of which isoptionally substituted with one or more R⁷;

R¹² is independently selected at each occurrence from R⁷; and

n is an integer from 0 to 3.

In some embodiments, for a compound of Formula (I-A) or (I-B), R¹¹ isC₁₋₆ alkyl, such as C₁₋₄ alkyl. In some embodiments, R¹¹ is selectedfrom methyl, ethyl, iso-propyl and tert-butyl. In some embodiments, R¹¹is selected from C₁₋₄ alkyl and C₃₋₁₂ cycloalkyl, each of which isoptionally substituted with one or more R⁷. In some embodiments, R¹¹ is—CH₃. In some embodiments, R¹¹ is selected from R⁷.

In some embodiments, for a compound of Formula (I-A) or (I-B), R¹² isindependently selected at each occurrence from halogen, —CN, alkoxy,haloalkoxy, alkyl and haloalkyl. In some embodiments, R¹² isindependently selected at each occurrence from halogen, —CN, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkyl and C₁₋₄ haloalkyl. In someembodiments, R¹² is independently selected at each occurrence fromhalogen, —CN, C₁₋₄ alkoxy, C₁₋₄ fluoroalkoxy, C₁₋₄ alkyl and C₁₋₄haloalkyl. In some embodiments, R¹² is independently selected at eachoccurrence from halogen, —CN, C₁₋₄ alkyl and C₁₋₃ haloalkyl. In someembodiments, R¹² is independently selected at each occurrence from F,—CN, —CH₃ and —CF₃. In some embodiments, R¹² is independently selectedat each occurrence from halogen, —CN, —CH₃ and —CF₃.

In some embodiments, for a compound of Formula (I-A) or (I-B), n is aninteger from 1 to 3, such as n is 1.

In some embodiments, for a compound of Formula (I-A) or (I-B):

R¹¹ is selected from C₁₋₆ alkyl, optionally substituted with one or moreR⁷;

R¹² is independently selected at each occurrence from halogen, —CN, C₁₋₄alkyl and C₁₋₃ haloalkyl; and

n is an integer from 1 to 3.

In some embodiments, for a compound of Formula (I-A) or (I-B):

R¹¹ is selected from C₁₋₆ alkyl and C₃₋₁₂ carbocycle, each of which isoptionally substituted with one or more R⁷;

R¹² is independently selected at each occurrence from halogen, —CN,alkoxy, haloalkoxy, alkyl and haloalkyl; and

n is an integer from 0 to 3.

In some embodiments, a compound of Formula (I) is represented by Formula(I-C):

or a pharmaceutically acceptable salt thereof, wherein:

Z is selected from C₃₋₁₂ cycloalkyl and 3- to 12-memberedheterocycloalkyl, each of which is optionally substituted with one ormore R⁷.

In some embodiments, for a compound of Formula (I-C), Z is selected fromC₃₋₁₂ monocyclic cycloalkyl or C₅₋₁₂ fused bicyclic cycloalkyl, each ofwhich is optionally substituted with one or more R⁷. In someembodiments, Z is C₅₋₁₂ fused bicyclic cycloalkyl, optionallysubstituted with one or more R⁷. In some embodiments, Z is selected fromC₃₋₁₂ monocyclic cycloalkyl or C₅₋₁₂ bicyclic cycloalkyl, each of whichis optionally substituted with one or more R⁷. In some embodiments, Z issubstituted with one or more substituents independently selected fromhalogen, —CN, C₁₋₄ alkyl and C₁₋₃ haloalkyl. In some embodiments, Z isselected from

In some embodiments, for a compound of Formula (I), (I-A), (I-B) or(I-C), R¹ is selected from hydrogen and C₁₋₆ alkyl, wherein the C₁₋₆alkyl is optionally substituted with one or more R⁷. In someembodiments, R¹ is selected from hydrogen and —CH₃. In some embodiments,R¹ is C₁₋₆ alkyl, such as —CH₃.

In some embodiments, for a compound of Formula (I), (I-A), (I-B) or(I-C), W³ is N. In some embodiments, W² is N or CH, such as W² is N. Insome embodiments, W¹ is N. In some embodiments, W³ is N and W² and W¹are independently N or CH. In some embodiments, W¹ is CH, W² is N and W³is N. In some embodiments, W¹ is N, W² is CH and W³ is N. In someembodiments, W¹, W² and W³ are each N.

In some embodiments, for a compound of Formula (I), (I-A), (I-B) or(I-C), R³ is selected from halogen and cyano; and C₁₋₆ alkyl, aryl,heteroaryl and benzyl, each of which is optionally substituted with oneor more R⁷. In some embodiments, R³ is selected from halogen, —CN, C₁₋₃alkyl and C₁₋₃ haloalkyl. In some embodiments, R³ is selected from —Cland —CN.

In some embodiments, for a compound of Formula (I), (I-A), (I-B) or(I-C), at least one of R⁴ and R⁵ is C₁₋₆ alkyl, optionally substitutedat each occurrence with one or more substituents selected from halogen,—OR⁸, —S—S—R⁸, —S—C(O)R⁸, —OC(O)R⁸, —OC(O)OR⁸ and —P(O)(OR⁸)₂.

In some embodiments, for a compound of Formula (I), (I-A), (I-B) or(I-C), R⁴ and R⁵ are independently selected from C₁₋₆ alkyl, optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, —OR⁸, —S—S—R⁸, —S—C(O)R⁸, —OC(O)R⁸, —OC(O)OR⁸ and—P(O)(OR⁸)₂. In some embodiments, R⁴ and R⁵ are independently selectedfrom —CH₂OC(O)R⁸ and —CH₂OC(O)OR⁸. In some embodiments, R⁴ and R⁵ areindependently selected from —CH₂OC(O)C(CH₃)₃, —CH₂OC(O)OCH(CH₃)₂,—CH₂OC(O)CH₃, —CH₂CH₂—S—S—(CH₂)₂OH and —CH₂CH₂—S—C(O)CH₃.

In some embodiments, for a compound of Formula (I), (I-A), (I-B) or(I-C), R⁴ is phenyl, optionally substituted with —OR⁸; R⁵ is C₁₋₆ alkylsubstituted with one or more substituents selected from —OC(O)R⁸,—C(O)OR⁸, and —OC(O)OR⁸; and R⁸ is C₁₋₆ alkyl.

In some embodiments, for a compound of Formula (I), (I-A), (I-B) or(I-C), X and Y are each —O—. In some embodiments, one of X and Y is —O—and the other one of X and Y is —NR⁸—.

In some embodiments, for a compound of Formula (I), (I-A), (I-B) or(I-C): W¹ is selected from N and CR⁶; W² is selected from N and CH; W³is N; R¹ is selected from hydrogen and C₁₋₄ alkyl; R³ is selected fromhalogen and cyano; and R⁶ is selected from halogen, cyano and C₁₋₄alkyl.

In some embodiments, for a compound of Formula (I), (I-A), (I-B) or(I-C), —X—R⁴ and —Y—R⁵ are each —OH.

In some embodiments, for a compound of Formula (I), (I-A), (I-B) or(I-C), at least one of R⁴ and R⁵ is selected from C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸,—S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂,—NR⁸S(═O)₂NR⁹R¹⁰, —S—S—R⁸, —S—C(O)R⁸, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,—OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,—NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,—P(O)(R⁸)₂, —OP(O)(OR⁸)₂, ═O, ═S, ═N(R⁸); and C₃₋₁₂ carbocycle, and 3-to 12-membered heterocycle, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, C₁₋₆ alkyl, —OR⁸, —OC(O)R⁸, and —C(O)R⁸.

In some embodiments, for a compound of Formula (I), (I-A), (I-B) or(I-C), R⁴ and R⁵ are independently selected from C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸,—S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂,—NR⁸S(═O)₂NR⁹R¹⁰, —S—S—R⁸, —S—C(O)R⁸, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,—OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,—NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,—P(O)(R⁸)₂, —OP(O)(OR⁸)₂, ═O, ═S, ═N(R⁸); and C₃₋₁₂ carbocycle, and 3-to 12-membered heterocycle, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, C₁₋₆ alkyl, —OR⁸, —OC(O)R⁸, and —C(O)R⁸.

In some embodiments, for a compound of Formula (I), (I-A), (I-B) or(I-C), R⁴ and R⁵ are independently selected from C₁₋₆ alkyl substitutedwith one or more substituents selected from halogen, —OC(O)R⁸,—OC(O)OR⁸, —S—S—R⁸, —S—C(O)R⁸, —OR⁸, and —P(O)(OR⁸)₂. In someembodiments, R⁴ and R⁵ are independently selected from hydrogen and C₁₋₆alkyl, wherein each C₁₋₆ alkyl is optionally substituted at eachoccurrence with one or more substituents selected from halogen,—OC(O)R⁸, —OC(O)OR⁸, —S—S—R⁸, —S—C(O)R⁸, —OR⁸, and —P(O)(OR⁸)₂. In someembodiments, R⁴ and R⁵ are independently selected from C₁₋₆ alkylsubstituted with one or more substituents selected from —OC(O)R⁸ and—OC(O)OR⁸. In some embodiments, R⁴ and R⁵ are independently selectedfrom C₁ alkyl substituted with one or more substituents selected from—OC(O)R⁸ and —OC(O)OR⁸, wherein R⁸ is C₁₋₆ alkyl. In some embodiments,R⁴ and R⁵ are independently selected from —CH₂OC(O)C(CH₃)₃,—CH₂OC(O)OCH(CH₃)₂, and —CH₂OC(O)CH₃. In some embodiments, R⁴ and R⁵ areeach —CH₂OC(O)C(CH₃)₃. In some embodiments, R⁴ and R⁵ are each—CH₂OC(O)OCH(CH₃)₂.

In some embodiments, for a compound of Formula (I), (I-A), (I-B) or(I-C), R⁴ and R⁵ are independently selected from C₁₋₆ alkyl substitutedwith one or more substituents selected from —S—S—R⁸, and —S—C(O)R⁸. Insome embodiments, R⁴ and R⁵ are independently selected from—CH₂CH₂—S—S—(CH₂)₂OH and —CH₂CH₂—S—C(O)CH₃. In some embodiments, R⁴ andR⁵ are each —CH₂CH₂—S—S—(CH₂)₂OH. In some embodiments, R⁴ and R⁵ areeach —CH₂CH₂—S—C(O)CH₃.

In some embodiments, for a compound of Formula (I), (I-A), (I-B) or(I-C), R⁴ and R⁵ are independently selected from C₃₋₁₂ carbocycle, suchas phenyl, wherein the C₃₋₁₂ carbocycle is optionally substituted withone or more substituents selected from halogen, C₁₋₆ alkyl, —OR⁸,—OC(O)R⁸, —C(O)OR⁸, and —C(O)R⁸. In some embodiments, R⁴ and R⁵ areindependently selected from phenyl, wherein the phenyl is optionallysubstituted with —OR⁸, such as phenyl substituted with —OCH₂CH₃. In someembodiments, one of R⁴ and R⁵ is selected from C₃₋₁₂ carbocycle, such asphenyl and benzyl, and the other of R⁴ and R⁵ is selected from C₁₋₆alkyl substituted with one or more substituents selected from —OC(O)R⁸,—C(O)OR⁸, and —OC(O)OR⁸, wherein R⁸ is C₁₋₆ alkyl.

In some embodiments, for a compound of Formula (I), (I-A), (I-B) or(I-C), R⁴ and R⁵ are independently selected from hydrogen and C₁₋₆alkylene-OR²⁰, wherein R²⁰ at each occurrence is independently selectedfrom C₇₋₂₀ alkyl and C₇₋₂₀ alkenyl. In some embodiments, one of R⁴ or R⁵is selected from —C₁₋₃alkylene-O—C₇₋₂₀alkyl and—C₁₋₃alkylene-O—C₇₋₂₀alkenyl, such as one of R⁴ or R⁵ is selected fromhexadecyloxypropyl (—CH₂(CH₂)₂O(CH₂)₁₅CH₃), octadecyloxyethyl(—CH₂CH₂O(CH₂)₁₇CH₃), oleyoxyethyl (—CH₂CH₂O(CH₂)₈CH═CH(CH₂)₇CH₃), andoleyoxypropyl (—CH₂(CH₂)₂O(CH₂)₈CH═CH(CH₂)₇CH₃), and the other of R⁴ andR⁵ is hydrogen.

In some embodiments, for a compound of Formula (I), (I-A), (I-B) or(I-C), R⁴ and R⁵ are taken together with the atoms to which they areattached to form a heterocycle, optionally substituted with one or moreR⁷. In some embodiments, the heterocycle is a 5- or 6-memberedheterocycle. In some embodiments, R⁴ and R⁵ are taken together with theatoms to which they are attached to form a heterocycle selected from:

In some embodiments, R⁷ is a halogen.

In some embodiments, for a compound of Formula (I), (I-A), (I-B) or(I-C), X and Y are each —O—. In some embodiments, one of X and Y is —O—and the other one of X and Y is —N(R⁸)—. In some embodiments, at leastone of —X—R⁴ and —Y—R⁵ comprises an amino acid or an amino acid ester,such as an L-alanine ester, e.g., —NHCH(CH₃)C(O)OCH(CH₃)₂ and—NHCH(CH₃)C(O)OCH₂CH₃. In some embodiments, at least one of —X—R⁴ and—Y—R⁵ comprises alanine, serine, phenylalanine, valine, or two or morethereof.

In some embodiments, for a compound of Formula (I), (I-A), (I-B) or(I-C), —X—R⁴ and —Y—R⁵ are independently selected from: —OH, —O—CH₃,—O—CH₂CH₃, —O—CH₂-Ph, —O-Ph,

In some embodiments, —X—R⁴ and —Y—R⁵ are different, such as —X—R⁴ is —OHand —Y—R⁵ is —O(CH₂)₃O(CH₂)₁₅CH₃. In some embodiments, one of —X—R⁴ and—Y—R⁵ is —OH, and the other one of —X—R⁴ and —Y—R⁵ is selected from

In some embodiments, —X—R⁴ and —Y—R⁵ are selected from the samemoieties, for example, —X—R⁴ is

and —Y—R⁵ is

or —X—R⁴ is

and —Y—R⁵ is

In some embodiments, —X—R⁴ and —Y—R⁵ are each —O—CH₃, —O—CH₂CH₃,—O—CH₂Ph, —OPh,

In some embodiments, for a compound of Formula (I), (I-A), (I-B) or(I-C), —X—R⁴ is selected from: —OH, —OCH₃, —OCH₂CH₃, —OCH₂Ph, —OPh,

and —Y—R⁵ is selected from —OCH₃, —OCH₂CH₃, —OCH₂Ph, —OPh,

In some embodiments, for a compound of Formula (I), (I-A), (I-B) or(I-C):

W¹ and W² are each independently selected from N and CH, wherein atleast one of W¹ and W² is N;

W³ is N;

R¹ is selected from hydrogen and C₁₋₆ alkyl; wherein the C₁₋₆ alkyl isoptionally substituted with one or more R⁷;

R³ is selected from halogen, —CN, C₁₋₃ alkyl and C₁₋₃ haloalkyl;

X and Y are each —O—; and

R⁴ and R⁵ are each hydrogen.

In some embodiments, for a compound of Formula (I), (I-A), (I-B) or(I-C):

W¹ and W² are CH;

W³ is N;

R¹ is selected from hydrogen and C₁₋₆ alkyl; wherein the C₁₋₆ alkyl isoptionally substituted with one or more R⁷;

R³ is selected from halogen, —CN, C₁₋₃ alkyl, aryl, heteroaryl and C₁₋₃haloalkyl;

X and Y are each —O—; and

R⁴ and R⁵ are each hydrogen.

In some embodiments, for a compound of Formula (I), (II-A), (II-B) or(III):

W¹ and W² are each independently selected from N and CH, wherein atleast one of W¹ and W² is N;

W³ is N;

R¹ is selected from hydrogen and C₁₋₆ alkyl; wherein the C₁₋₆ alkyl isoptionally substituted with one or more R⁷;

R³ is selected from halogen, —CN, C₁₋₃ alkyl and C₁₋₃ haloalkyl;

X and Y are independently selected from —O— and —NR⁸—, wherein at leastone of X and Y is —O—; and

R⁴ and R⁵ are independently selected from C₁₋₆ alkyl substituted withone or more substituents selected from halogen, —OC(O)R⁸, —OC(O)OR⁸,—S—S—R⁸, —S—C(O)R⁸, —OR⁸, and —P(O)(OR⁸)₂.

In some embodiments, for a compound of Formula (I), (I-A), (I-B) or(I-C):

W¹ and W² are CH;

W³ is N;

R¹ is selected from hydrogen and C₁₋₆ alkyl; wherein the C₁₋₆ alkyl isoptionally substituted with one or more R⁷;

R³ is selected from halogen, —CN, C₁₋₃ alkyl, aryl, heteroaryl and C₁₋₃haloalkyl;

X and Y are independently selected from —O— and —NR⁸—, wherein at leastone of X and Y is —O—; and

R⁴ and R⁵ are independently selected from C₁₋₆ alkyl substituted withone or more substituents selected from halogen, —OC(O)R⁸, —OC(O)OR⁸,—S—S—R⁸, —S—C(O)R⁸, —OR⁸, and —P(O)(OR⁸)₂.

In some embodiments, for a compound of Formula (I), (I-A), (I-B) or(I-C):

W¹ and W² are each independently selected from N and CH, wherein atleast one of W¹ and W² is N;

W³ is N;

R¹ is selected from hydrogen and C₁₋₆ alkyl; wherein the C₁₋₆ alkyl isoptionally substituted with one or more R⁷;

R³ is selected from halogen, —CN, C₁₋₃ alkyl and C₁₋₃ haloalkyl; and

—X—R⁴ and —Y—R⁵ are independently selected from:

—OH, —O—CH₃, —O—CH₂CH₃, —O—CH₂-Ph, —O-Ph,

wherein at least one of —X—R⁴ and —Y—R⁵ is not —OH.

In certain aspects, the present disclosure provides a compound ofFormula (I-A) or (I-B):

or a pharmaceutically acceptable salt thereof, wherein:

W¹, W² and W³ are each independently selected from N and CH, wherein atleast one of W¹, W² and W³ is N;

R¹ is selected from hydrogen and C₁₋₆ alkyl;

R³ is selected from halogen and cyano;

—X—R⁴ is selected from —OH, —OCH₃, —OCH₂CH₃, —OCH₂Ph, —OPh,

—Y—R⁵ is selected from —OCH₃, —OCH₂CH₃, —OCH₂Ph, —OPh,

R⁷ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸,        —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,        —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,        —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,        —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰,        —P(O)(OR⁸)₂, —P(O)(R⁸)₂, ═O, ═S, and ═N(R⁸);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁸,        —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to        12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁷ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁸, —SR⁸,        —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl;

R⁸ is independently selected at each occurrence from hydrogen; and C₁₋₂₀alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁹ and R¹⁰ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁷;

R¹¹ is selected from C₁₋₆ alkyl and C₃₋₁₂ carbocycle, each of which isoptionally substituted with one or more R⁷;

R¹² is independently selected at each occurrence from halogen, —CN, C₁₋₄alkyl and C₁₋₃ haloalkyl; and

n is an integer from 0 to 3.

In certain aspects, the present disclosure provides a compound ofFormula (I-A) or (I-B):

or a pharmaceutically acceptable salt thereof, wherein:

W¹, W² and W³ are each independently selected from N and CH, wherein atleast one of W¹, W² and W³ is N;

R¹ is selected from hydrogen and C₁₋₆ alkyl; wherein the C₁₋₆ alkyl isoptionally substituted with one or more R⁷;

R³ is selected from halogen and cyano;

—X—R⁴ is selected from —OH, —OCH₃, —OCH₂CH₃, —OCH₂Ph,

—Y—R⁵ is selected from —OCH₃, —OCH₂CH₃, —OCH₂Ph, —OPh,

R⁷ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸,        —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,        —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,        —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,        —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰,        —P(O)(OR⁸)₂, —P(O)(R⁸)₂, ═O, ═S, and ═N(R⁸);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁸,        —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to        12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁷ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁸, —SR⁸,        —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl;

R⁸ is independently selected at each occurrence from hydrogen; and C₁₋₂₀alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁹ and R¹⁰ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁷;

R¹¹ is selected from C₁₋₆ alkyl and C₃₋₁₂ carbocycle, each of which isoptionally substituted with one or more R⁷;

R¹² is independently selected at each occurrence from halogen, —CN, C₁₋₄alkyl and C₁₋₃ haloalkyl; and

n is an integer from 0 to 3.

In certain aspects, the present disclosure provides a compound ofFormula (II):

or a pharmaceutically acceptable salt thereof, wherein:

W¹, W² and W³ are each independently selected from N and CR⁶, wherein atleast one of W¹, W² and W³ is N;

R¹ is selected from hydrogen; and C₁₋₆ alkyl and C₃₋₁₂ carbocycle, eachof which is optionally substituted with one or more R⁷;

R² is selected from C₁₋₆ alkyl, C₃₋₁₂ carbocycle, 3- to 12-memberedheterocycle and benzyl, each of which is optionally substituted with oneor more R⁷; or

R¹ and R² are taken together with the nitrogen atom to which they areattached to form a 3- to 12-membered heterocycle, optionally substitutedwith one or more R⁷;

R³ is selected from hydrogen, halogen and cyano; and C₁₋₆ alkyl, C₃₋₁₂carbocycle, 3- to 12-membered heterocycle and benzyl, each of which isoptionally substituted with one or more R⁷;

A is selected from —S—, —S(═O)— and —S(═O)₂—;

X and Y are independently selected from —O— and —NR⁸—;

R⁴ and R⁵ are independently selected from:

-   -   hydrogen; and    -   C₁₋₆ alkyl and phenyl, each of which is independently optionally        substituted at each occurrence with one or more substituents        selected from halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰,        —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,        —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —S—S—R⁸, —S—C(O)R⁸, —C(O)R⁸,        —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰,        —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰,        —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂, —P(O)(R⁸)₂, —OP(O)(OR⁸)₂,        ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to 12-membered        heterocycle;

R⁶ is selected from hydrogen, halogen and cyano; and C₁₋₆ alkyl,optionally substituted with one or more R⁷;

R⁷ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸,        —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,        —NR⁸S(═O)₂N(R⁸)₂, —NR S(═O)₂NR⁹R¹⁰, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,        —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,        —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰,        —P(O)(OR⁸)₂, —P(O)(R⁸)₂, ═O, ═S, and ═N(R⁸);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁸,        —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to        12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁷ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁸, —SR⁸,        —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl;

R⁸ is independently selected at each occurrence from hydrogen; and C₁₋₂₀alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle; and

R⁹ and R¹⁰ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁷.

In some embodiments, for a compound of Formula (II), R¹ is selected fromhydrogen and C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionallysubstituted with one or more R⁷. In some embodiments, R¹ is selectedfrom hydrogen and —CH₃.

In some embodiments, for a compound of Formula (II), R² is selected fromC₁₋₆ alkyl, C₃₋₁₂ carbocycle, 3- to 12-membered heterocycle and benzyl,each of which is optionally substituted with one or more substituentsindependently selected from halogen, —CN, C₁₋₄ alkyl, C₁₋₃ haloalkyl,—OH and —NH₂. In some embodiments, R² is benzyl, optionally substitutedwith one or more R⁷. In some embodiments, R² is benzyl, optionallysubstituted with one or more substituents independently selected fromhalogen, —CN, C₁₋₄ alkyl, C₁₋₃ haloalkyl, —OH and —NH₂. In someembodiments, R² is C₁₋₆ alkyl or C₃₋₈ cycloalkyl, each of which isoptionally substituted with one or more substituents independentlyselected from halogen, —CN, C₁₋₃ haloalkyl, —OH, —NH₂, optionallysubstituted phenyl and optionally substituted pyridyl. In someembodiments, R² is C₃₋₈ cycloalkyl, such as cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl. In some embodiments, R² is C₁₋₄ alkyl, suchas methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl ortert-butyl. In some embodiments, R² is C₁₋₆ alkyl, C₃₋₈ cycloalkyl, orbenzyl, each of which is optionally substituted with one or moresubstituents independently selected from halogen, —CN, C₁₋₄ alkyl, C₁₋₃haloalkyl, —OH and —NH₂.

In some embodiments, for a compound of Formula (II), R¹ and R² are takentogether with the nitrogen atom to which they are attached to form a 3-to 12-membered heterocycle, optionally substituted with one or more R⁷,such as one or more substituents independently selected from halogen,—CN, C₁₋₄ alkyl, C₁₋₃ haloalkyl, —OH and —NH₂. In some embodiments, R¹and R² are taken together with the nitrogen atom to which they areattached to form an optionally substituted 3- to 7-membered monocyclicheterocycloalkyl or an optionally substituted 5- to 12-membered fusedbicyclic heterocycloalkyl. The 3- to 12-membered heterocycle formed byR¹, R² and the nitrogen atom to which they are attached may be selectedfrom

In some embodiments, a compound of Formula (II) is represented byFormula (II-A) or (II-B):

or a pharmaceutically acceptable salt thereof, wherein:

R¹¹ is selected from hydrogen, C₁₋₆ alkyl and C₃₋₁₂ carbocycle, each ofwhich is optionally substituted with one or more R⁷; R¹² isindependently selected at each occurrence from R⁷; and n is an integerfrom 0 to 3.

In some embodiments, for a compound of Formula (II-A) or (II-B), R¹¹ isselected from C₁₋₆ alkyl and C₃₋₁₂ carbocycle, each of which isoptionally substituted with one or more R⁷; R¹² is independentlyselected at each occurrence from R⁷; and n is an integer from 0 to 3.

In some embodiments, for a compound of Formula (II-A) or (II-B), R¹¹ isC₁₋₆ alkyl, such as C₁₋₄ alkyl. In some embodiments, R¹¹ is selectedfrom methyl, ethyl, iso-propyl and tert-butyl. In some embodiments, R¹¹is selected from C₁₋₄ alkyl and C₃₋₁₂ cycloalkyl, each of which isoptionally substituted with one or more R⁷. In some embodiments, R¹¹ is—CH₃. In some embodiments, R¹¹ is selected from R⁷.

In some embodiments, for a compound of Formula (II-A) or (II-B), R¹² isindependently selected at each occurrence from halogen, —CN, alkoxy,haloalkoxy, alkyl and haloalkyl. In some embodiments, R¹² isindependently selected at each occurrence from halogen, —CN, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkyl and C₁₋₄ haloalkyl. In someembodiments, R¹² is independently selected at each occurrence fromhalogen, —CN, C₁₋₄ alkoxy, C₁₋₄ fluoroalkoxy, C₁₋₄ alkyl and C₁₋₄haloalkyl. In some embodiments, R¹² is independently selected at eachoccurrence from halogen, —CN, C₁₋₄ alkyl and C₁₋₃ haloalkyl. In someembodiments, R¹² is independently selected at each occurrence from F,—CN, —CH₃ and —CF₃. In some embodiments, R¹² is independently selectedat each occurrence from halogen, —CN, —CH₃ and —CF₃.

In some embodiments, for a compound of Formula (II-A) or (II-B), n is aninteger from 1 to 3, such as n is 1.

In some embodiments, for a compound of Formula (II-A) or (II-B):

R¹¹ is selected from C₁₋₆ alkyl, optionally substituted with one or moreR⁷;

R¹² is independently selected at each occurrence from halogen, —CN, C₁₋₄alkyl and C₁₋₃ haloalkyl; and

n is an integer from 1 to 3.

In some embodiments, for a compound of Formula (II-A) or (II-B):

R¹¹ is selected from C₁₋₆ alkyl and C₃₋₁₂ carbocycle, each of which isoptionally substituted with one or more R⁷;

R¹² is independently selected at each occurrence from halogen, —CN,alkoxy, haloalkoxy, alkyl and haloalkyl; and

n is an integer from 0 to 3.

In some embodiments, a compound of Formula (II) is represented byFormula (II-C):

or a pharmaceutically acceptable salt thereof, wherein:

Z is selected from C₃₋₁₂ cycloalkyl and 3- to 12-memberedheterocycloalkyl, each of which is optionally substituted with one ormore R⁷.

In some embodiments, for a compound of Formula (II-C), Z is selectedfrom C₃₋₁₂ monocyclic cycloalkyl or C₅₋₁₂ fused bicyclic cycloalkyl,each of which is optionally substituted with one or more R⁷. In someembodiments, Z is C₅₋₁₂ fused bicyclic cycloalkyl, optionallysubstituted with one or more R⁷. In some embodiments, Z is selected fromC₃₋₁₂ monocyclic cycloalkyl or C₅₋₁₂ bicyclic cycloalkyl, each of whichis optionally substituted with one or more R⁷. In some embodiments, Z issubstituted with one or more substituents independently selected fromhalogen, —CN, C₁₋₄ alkyl and C₁₋₃ haloalkyl. In some embodiments, Z isselected from

In some embodiments, for a compound of Formula (II), (II-A), (II-B) or(II-C), R¹ is selected from hydrogen and C₁₋₆ alkyl, wherein the C₁₋₆alkyl is optionally substituted with one or more R⁷. In someembodiments, R¹ is selected from hydrogen and —CH₃. In some embodiments,R¹ is C₁₋₆ alkyl, such as —CH₃.

In some embodiments, for a compound of Formula (II), (II-A), (II-B) or(II-C), W³ is N. In some embodiments, W² is N or CH, such as W² is N. Insome embodiments, W¹ is N or CH, such as W¹ is N. In some embodiments,W¹ is CH. In some embodiments, W³ is N and W² and W¹ are independently Nor CH. In some embodiments, W¹ is CH, W² is N and W³ is N. In someembodiments, W¹ is N, W² is CH and W³ is N. In some embodiments, W¹, W²and W³ are each N.

In some embodiments, for a compound of Formula (II), (II-A), (II-B) or(II-C), R³ is selected from hydrogen, halogen and cyano; and C₁₋₆ alkyl,aryl, heteroaryl and benzyl, each of which is optionally substitutedwith one or more R⁷. In some embodiments, R³ is selected from hydrogen,halogen, —CN, C₁₋₃ alkyl and C₁₋₃ haloalkyl. In some embodiments, R³ isselected from —H, —Cl and —CN. In some embodiments, R³ is selected fromhydrogen, halogen and cyano.

In some embodiments, for a compound of Formula (II), (II-A), (II-B) or(II-C), R³ is selected from halogen and cyano; and C₁₋₆ alkyl, aryl,heteroaryl and benzyl, each of which is optionally substituted with oneor more R⁷. In some embodiments, R³ is selected from halogen, —CN, C₁₋₃alkyl and C₁₋₃ haloalkyl. In some embodiments, R³ is selected from —Cland —CN. In some embodiments, R³ is selected from halogen and cyano.

In some embodiments, for a compound of Formula (II), (II-A), (II-B) or(II-C), A is selected from —S—, —S(═O)— and —S(═O)₂. In someembodiments, A is selected from —S(═O)— and —S(═O)₂. In someembodiments, A is selected from —S— and —S(═O)₂. In some embodiments, Ais selected from —S— and —S(═O)—. In some embodiments, A is —S—. In someembodiments, A is —S(═O)—. In some embodiments, A is —S(═O)₂.

In some embodiments, for a compound of Formula (II), (II-A), (II-B) or(II-C), at least one of R⁴ and R⁵ is C₁₋₆ alkyl, optionally substitutedat each occurrence with one or more substituents selected from halogen,—OR⁸, —S—S—R⁸, —S—C(O)R⁸, —OC(O)R⁸, —OC(O)OR⁸ and —P(O)(OR⁸)₂.

In some embodiments, for a compound of Formula (II), (II-A), (II-B) or(II-C), R⁴ and R⁵ are independently selected from C₁₋₆ alkyl, optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, —OR⁸, —S—S—R⁸, —S—C(O)R⁸, —OC(O)R⁸, —OC(O)OR⁸ and—P(O)(OR⁸)₂. In some embodiments, R⁴ and R⁵ are independently selectedfrom —CH₂OC(O)R⁸ and —CH₂OC(O)OR⁸. In some embodiments, R⁴ and R⁵ areindependently selected from —CH₂OC(O)C(CH₃)₃, —CH₂OC(O)OCH(CH₃)₂,—CH₂OC(O)CH₃, —CH₂CH₂—S—S—(CH₂)₂OH and —CH₂CH₂—S—C(O)CH₃.

In some embodiments, for a compound of Formula (II), (II-A), (II-B) or(II-C), R⁴ is phenyl, optionally substituted with —OR⁸; R⁵ is C₁₋₆ alkylsubstituted with one or more substituents selected from —OC(O)R⁸,—C(O)OR⁸, and —OC(O)OR⁸; and R⁸ is C₁₋₆ alkyl.

In some embodiments, for a compound of Formula (II), (II-A), (II-B) or(II-C), X and Y are each —O—. In some embodiments, one of X and Y is —O—and the other one of X and Y is —NR⁸—.

In some embodiments, for a compound of Formula (II), (II-A), (II-B) or(II-C): W¹ is selected from N and CR⁶; W² is selected from N and CH; W³is N; R¹ is selected from hydrogen and C₁₋₄ alkyl; R³ is selected fromhalogen and cyano; and R⁶ is selected from halogen, cyano and C₁₋₄alkyl.

In some embodiments, for a compound of Formula (II), (II-A), (II-B) or(II-C), —X—R⁴ and —Y—R⁵ are each —OH.

In some embodiments, for a compound of Formula (II), (II-A), (II-B) or(II-C), at least one of R⁴ and R⁵ is selected from C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸,—S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂,—NR⁸S(═O)₂NR⁹R¹⁰, —S—S—R⁸, —S—C(O)R⁸, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,—OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,—NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,—P(O)(R⁸)₂, —OP(O)(OR⁸)₂, ═O, ═S, ═N(R⁸); and C₃₋₁₂ carbocycle, and 3-to 12-membered heterocycle, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, C₁₋₆ alkyl, —OR⁸, —OC(O)R⁸, and —C(O)R⁸.

In some embodiments, for a compound of Formula (II), (II-A), (II-B) or(II-C), R⁴ and R⁵ are independently selected from C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸,—S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂,—NR⁸S(═O)₂NR⁹R¹⁰, —S—S—R⁸, —S—C(O)R⁸, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,—OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,—NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,—P(O)(R⁸)₂, —OP(O)(OR⁸)₂, ═O, ═S, ═N(R⁸); and C₃₋₁₂ carbocycle, and 3-to 12-membered heterocycle, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, C₁₋₆ alkyl, —OR⁸, —OC(O)R⁸, and —C(O)R⁸.

In some embodiments, for a compound of Formula (II), (II-A), (II-B) or(II-C), R⁴ and R⁵ are independently selected from C₁₋₆ alkyl substitutedwith one or more substituents selected from halogen, —OC(O)R⁸,—OC(O)OR⁸, —S—S—R⁸, —S—C(O)R⁸, —OR⁸, and —P(O)(OR⁸)₂. In someembodiments, R⁴ and R⁵ are independently selected from hydrogen and C₁₋₆alkyl, wherein each C₁₋₆ alkyl is optionally substituted at eachoccurrence with one or more substituents selected from halogen,—OC(O)R⁸, —OC(O)OR⁸, —S—S—R⁸, —S—C(O)R⁸, —OR⁸, and —P(O)(OR⁸)₂. In someembodiments, R⁴ and R⁵ are independently selected from C₁₋₆ alkylsubstituted with one or more substituents selected from —OC(O)R⁸ and—OC(O)OR⁸. In some embodiments, R⁴ and R⁵ are independently selectedfrom C₁ alkyl substituted with one or more substituents selected from—OC(O)R⁸ and —OC(O)OR⁸, wherein R⁸ is C₁₋₆ alkyl. In some embodiments,R⁴ and R⁵ are independently selected from —CH₂OC(O)C(CH₃)₃,—CH₂OC(O)OCH(CH₃)₂, and —CH₂OC(O)CH₃. In some embodiments, R⁴ and R⁵ areeach —CH₂OC(O)C(CH₃)₃. In some embodiments, R⁴ and R⁵ are each—CH₂OC(O)OCH(CH₃)₂.

In some embodiments, for a compound of Formula (II), (II-A), (II-B) or(II-C), R⁴ and R⁵ are independently selected from C₁₋₆ alkyl substitutedwith one or more substituents selected from —S—S—R⁸, and —S—C(O)R⁸. Insome embodiments, R⁴ and R⁵ are independently selected from—CH₂CH₂—S—S—(CH₂)₂OH and —CH₂CH₂—S—C(O)CH₃. In some embodiments, R⁴ andR⁵ are each —CH₂CH₂—S—S—(CH₂)₂OH. In some embodiments, R⁴ and R⁵ areeach —CH₂CH₂—S—C(O)CH₃.

In some embodiments, for a compound of Formula (II), (II-A), (II-B) or(II-C), R⁴ and R⁵ are independently selected from C₃₋₁₂ carbocycle, suchas phenyl, wherein the C₃₋₁₂ carbocycle is optionally substituted withone or more substituents selected from halogen, C₁₋₆ alkyl, —OR,—OC(O)R⁸, —C(O)OR⁸, and —C(O)R⁸. In some embodiments, R⁴ and R⁵ areindependently selected from phenyl, wherein the phenyl is optionallysubstituted with —OR⁸, such as phenyl substituted with —OCH₂CH₃. In someembodiments, one of R⁴ and R⁵ is selected from C₃₋₁₂ carbocycle, such asphenyl and benzyl, and the other of R⁴ and R⁵ is selected from C₁₋₆alkyl substituted with one or more substituents selected from —OC(O)R⁸,—C(O)OR⁸, and —OC(O)OR⁸, wherein R⁸ is C₁₋₆ alkyl.

In some embodiments, for a compound of Formula (II), (II-A), (II-B) or(II-C), R⁴ and R⁵ are independently selected from hydrogen andC₁₋₆alkylene-OR²⁰, wherein R²⁰ at each occurrence is independentlyselected from C₇₋₂₀alkyl and C₇₋₂₀alkenyl. In some embodiments, one ofR⁴ or R⁵ is selected from —C₁₋₃alkylene-O—C₇₋₂₀alkyl and—C₁₋₃alkylene-O—C₇₋₂₀alkenyl, such as one of R⁴ or R⁵ is selected fromhexadecyloxypropyl (—CH₂(CH₂)₂O(CH₂)₁₅CH₃), octadecyloxyethyl(—CH₂CH₂O(CH₂)₇CH₃), oleyoxyethyl (—CH₂CH₂O(CH₂)₈CH═CH(CH₂)₇CH₃), andoleyoxypropyl (—CH₂(CH₂)₂O(CH₂)₈CH═CH(CH₂)₇CH₃), and the other of R⁴ andR⁵ is hydrogen.

In some embodiments, for a compound of Formula (II), (II-A), (II-B) or(II-C), R⁴ and R⁵ are taken together with the atoms to which they areattached to form a heterocycle, optionally substituted with one or moreR⁷. In some embodiments, the heterocycle is a 5- or 6-memberedheterocycle. In some embodiments, R⁴ and R⁵ are taken together with theatoms to which they are attached to form a heterocycle selected from:

In some embodiments, R is a halogen.

In some embodiments, for a compound of Formula (II), (II-A), (II-B) or(II-C), X and Y are each —O—. In some embodiments, one of X and Y is —O—and the other one of X and Y is —N(R⁸)—. In some embodiments, at leastone of —X—R⁴ and —Y—R⁵ comprises an amino acid or an amino acid ester,such as an L-alanine ester, e.g., —NHCH(CH₃)C(O)OCH(CH₃)₂ and—NHCH(CH₃)C(O)OCH₂CH₃. In some embodiments, at least one of —X—R⁴ and—Y—R⁵ comprises alanine, serine, phenylalanine, valine, or two or morethereof.

In some embodiments, for a compound of Formula (II), (II-A), (II-B) or(II-C), —X—R⁴ and —Y—R⁵ are independently selected from:

—OH, —O—CH₃, —O—CH₂CH₃, —O—CH₂-Ph, —O-Ph,

In some embodiments, —X—R⁴ and —Y—R⁵ are different, such as —X—R⁴ is —OHand —Y—R⁵ is —O(CH₂)₃O(CH₂)₁₅CH₃. In some embodiments, one of —X—R⁴ and—Y—R⁵ is —OH, and the other one of —X—R⁴ and —Y—R⁵ is selected from

In some embodiments, —X—R⁴ and —Y—R⁵ are selected from the samemoieties, for example, —X—R⁴ is

and —Y—R⁵ is

or —X—R⁴ is

and —Y—R⁵ is

In some embodiments, —X—R⁴ and —Y—R⁵ are each —O—CH₃, —O—CH₂CH₃,—O—CH₂Ph,

In some embodiments, for a compound of Formula (I), (II-A), (II-B) or(II-C), —X—R⁴ is selected from: —OH, —OCH₃, —OCH₂CH₃, —OCH₂Ph, —OPh,

and —Y—R⁵ is selected from —OCH₃, —OCH₂CH₃, —OCH₂Ph, —OPh,

In some embodiments, for a compound of Formula (II), (II-A), (II-B) or(II-C):

W¹ and W² are each independently selected from N and CH, wherein atleast one of W¹ and W² is N;

W³ is N;

R¹ is selected from hydrogen and C₁₋₆ alkyl; wherein the C₁₋₆ alkyl isoptionally substituted with one or more R⁷;

R³ is selected from hydrogen, halogen, —CN, C₁₋₃ alkyl and C₁₋₃haloalkyl;

X and Y are each —O—; and

R⁴ and R⁵ are each hydrogen.

In some embodiments, for a compound of Formula (II), (II-A), (II-B) or(II-C):

W¹ and W² are each independently selected from N and CH, wherein atleast one of W¹ and W² is N;

W³ is N;

R¹ is selected from hydrogen and C₁₋₆ alkyl; wherein the C₁₋₆ alkyl isoptionally substituted with one or more R⁷;

R³ is selected from halogen, —CN, C₁₋₃ alkyl and C₁₋₃ haloalkyl;

X and Y are each —O—; and

R⁴ and R⁵ are each hydrogen.

In some embodiments, for a compound of Formula (II), (II-A), (II-B) or(II-C):

W¹ and W² are each independently selected from N and CH, wherein atleast one of W¹ and W² is N;

W³ is N;

R¹ is selected from hydrogen and C₁₋₆ alkyl; wherein the C₁₋₆ alkyl isoptionally substituted with one or more R⁷;

R³ is selected from hydrogen, halogen, —CN, C₁₋₃ alkyl and C₁₋₃haloalkyl;

X and Y are independently selected from —O— and —NR⁸—, wherein at leastone of X and Y is —O—; and

R⁴ and R⁵ are independently selected from C₁₋₆ alkyl substituted withone or more substituents selected from halogen, —OC(O)R⁸, —OC(O)OR⁸,—S—S—R⁸, —S—C(O)R⁸, —OR⁸, and —P(O)(OR⁸)₂.

In some embodiments, for a compound of Formula (II), (II-A), (II-B) or(II-C):

W¹ and W² are each independently selected from N and CH, wherein atleast one of W¹ and W² is N;

W³ is N;

R¹ is selected from hydrogen and C₁₋₆ alkyl; wherein the C₁₋₆ alkyl isoptionally substituted with one or more R⁷;

R³ is selected from halogen, —CN, C₁₋₃ alkyl and C₁₋₃ haloalkyl;

X and Y are independently selected from —O— and —NR⁸—, wherein at leastone of X and Y is —O—; and

R⁴ and R⁵ are independently selected from C₁₋₆ alkyl substituted withone or more substituents selected from halogen, —OC(O)R⁸, —OC(O)OR⁸,—S—S—R⁸, —S—C(O)R⁸, —OR⁸, and —P(O)(OR⁸)₂.

In some embodiments, for a compound of Formula (II), (II-A), (II-B) or(II-C):

W¹ and W² are each independently selected from N and CH, wherein atleast one of W¹ and W² is N;

W³ is N;

R¹ is selected from hydrogen and C₁₋₆ alkyl; wherein the C₁₋₆ alkyl isoptionally substituted with one or more R⁷;

R³ is selected from hydrogen, halogen, —CN, C₁₋₃ alkyl and C₁₋₃haloalkyl; and

—X—R⁴ and —Y—R⁵ are independently selected from:

—OH, —O—CH₃, —O—CH₂CH₃, —O—CH₂-Ph, —O-Ph,

wherein at least one of —X—R⁴ and —Y—R⁵ is not —OH.

In certain aspects, the present disclosure provides a compound ofFormula (II-A) or (II-B):

or a pharmaceutically acceptable salt thereof, wherein:

W¹, W² and W³ are each independently selected from N and CH, wherein atleast one of W¹, W² and W³ is N;

R¹ is selected from hydrogen and C₁₋₆ alkyl;

R³ is selected from hydrogen, halogen and cyano;

A is selected from —S—, —S(═O)— and —S(═O)₂—;

—X—R⁴ is selected from —OH, —OCH₃, —OCH₂CH₃, —OCH₂Ph, —OPh,

—Y—R⁵ is selected from —OCH₃, —OCH₂CH₃, —OCH₂Ph, —OPh,

R⁷ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸,        —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,        —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,        —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,        —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰,        —P(O)(OR⁸)₂, —P(O)(R⁸)₂, ═O, ═S, and ═N(R⁸);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁸,        —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to        12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁷ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁸, —SR⁸,        —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl;

R⁸ is independently selected at each occurrence from hydrogen; and C₁₋₂₀alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁹ and R¹⁰ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁷;

R¹¹ is selected from C₁₋₆ alkyl and C₃₋₁₂ carbocycle, each of which isoptionally substituted with one or more R⁷;

R¹² is independently selected at each occurrence from halogen, —CN, C₁₋₄alkyl and C₁₋₃ haloalkyl; and

n is an integer from 0 to 3.

In certain aspects, the present disclosure provides a compound ofFormula (II-A) or (II-B):

or a pharmaceutically acceptable salt thereof, wherein:

W¹, W² and W³ are each independently selected from N and CH, wherein atleast one of W¹, W² and W³ is N;

R¹ is selected from hydrogen and C₁₋₆ alkyl; wherein the C₁₋₆ alkyl isoptionally substituted with one or more R⁷;

R³ is selected from hydrogen, halogen and cyano;

A is selected from —S—, —S(═O)— and —S(═O)₂—;

—X—R⁴ is selected from —OH, —OCH₃, —OCH₂CH₃, —OCH₂Ph, —OPh,

—Y—R⁵ is selected from —OCH₃, —OCH₂CH₃, —OCH₂Ph, —OPh,

R⁷ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸,        —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,        —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,        —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,        —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰,        —P(O)(OR⁸)₂, —P(O)(R⁸)₂, ═O, ═S, and ═N(R⁸);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁸,        —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to        12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁷ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁸, —SR⁸,        —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl;

R⁸ is independently selected at each occurrence from hydrogen; and C₁₋₂₀alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁹ and R¹⁰ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR;

R¹¹ is selected from C₁₋₆ alkyl and C₃₋₁₂ carbocycle, each of which isoptionally substituted with one or more R⁷;

R¹² is independently selected at each occurrence from halogen, —CN, C₁₋₄alkyl and C₁₋₃ haloalkyl; and

n is an integer from 0 to 3.

In certain aspects, the present disclosure provides a compound ofFormula (III):

or a pharmaceutically acceptable salt thereof, wherein:

W¹ is selected from N, NR⁸, CR⁶, and S;

W² and W³ are each independently selected from N and CR⁶;

W⁴ and W⁵ are each independently selected from N and C;

W⁶ is selected from N, CR⁶, and S;

-   -   wherein at least one of W¹, W², W³, W⁴, W⁵, and W⁶ is N, and        provided that:        -   when W¹, W², W³, W⁵, and W⁶ are N, W⁴ is not N; and        -   when either W¹ or W⁶ is S, the other is CR⁶;

R¹⁵ is selected from —NR¹R², —OR¹, —SR¹ and —CN; and C₃₋₁₂ memberedcarbocycle and 3- to 12-membered heterocycle, each of which isoptionally substituted with one or more R⁷;

R¹ is selected from hydrogen; and C₁₋₆ alkyl and C₃₋₁₂ carbocycle, eachof which is optionally substituted with one or more R⁷;

R² is selected from C₁₋₆ alkyl, C₃₋₁₂ carbocycle, 3- to 12-memberedheterocycle and benzyl, each of which is optionally substituted with oneor more R⁷; or

R¹ and R² are taken together with the nitrogen atom to which they areattached to form a 3- to 12-membered heterocycle, optionally substitutedwith one or more R⁷;

R³ is selected from hydrogen, halogen, cyano, —N(R⁸)₂ and —OR⁸; and C₁₋₆alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, 3- to 12-memberedheterocycle and benzyl, each of which is optionally substituted with oneor more R⁷;

A is selected from —O—, —S—, —S(═O)— and —S(═O)₂—;

X and Y are independently selected from —O— and —NR⁸—;

R⁴ and R⁵ are independently selected from:

-   -   hydrogen; and    -   C₁₋₆ alkyl, phenyl, and 3- to 12-membered heterocycle, each of        which is independently optionally substituted at each occurrence        with one or more substituents selected from halogen, —NO₂, —CN,        —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸,        —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂,        —NR⁸S(═O)₂NR⁹R¹⁰, —S—S—R⁸, —S—C(O)R⁸, —C(O)R⁸, —C(O)OR⁸,        —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸,        —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂,        —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂, —P(O)(R⁸)₂, —OP(O)(OR⁸)₂, ═O, ═S,        ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle; or

R⁴ and R⁵ are taken together with the atoms to which they are attachedto form a 3- to 12-membered heterocycle, optionally substituted with oneor more R⁷;

R⁶ is selected from hydrogen, halogen and cyano; and C₁₋₆ alkyl,optionally substituted with one or more R⁷;

R⁷ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸,        —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,        —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,        —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,        —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰,        —P(O)(OR⁸)₂, —P(O)(R⁸)₂, ═O, ═S, and ═N(R⁸);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁸,        —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to        12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁷ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁸, —SR⁸,        —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,        —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,        —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,        —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,        —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,        —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl;

R⁸ is independently selected at each occurrence from hydrogen; and C₁₋₂₀alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁹ and R¹⁰ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁷;

R¹³ is selected from hydrogen and C₁₋₆ alkyl; and

R¹⁴ is selected from hydrogen and R⁷.

In some embodiments, for a compound of Formula (III), one of W¹ or W⁶ isS. In some embodiments, one of W¹ or W⁶ is S and W⁵ is C. In someembodiments, W⁶ and W⁵ are N and W¹ is CH. In some embodiments, W¹ isNH, W⁶ is CH, and W⁵ is C. In some embodiments, W¹ is selected from N,NH, CR⁶ and S.

In some embodiments, a compound of Formula (III) is represented by thestructure

In some embodiments, a compound of Formula (III) is represented by thestructure

In some embodiments, a compound of Formula (III) is represented by thestructure

In some embodiments, a compound of Formula (III) is represented by thestructure

optionally wherein R⁶ is halogen. In some embodiments, a compound ofFormula (III) is represented by the structure

In some embodiments, a compound of Formula (III) is represented by thestructure

In some embodiments, a compound of Formula (III) is represented by thestructure

optionally wherein R⁶ is methyl. In some embodiments, a compound ofFormula (III) is represented by the structure

optionally wherein R⁶ is methyl.

In some embodiments, for a compound of Formula (III), R¹⁵ is selectedfrom —OR¹ and SR¹, optionally wherein R¹ is selected from C₁₋₆ alkyl andC₃₋₁₂ carbocycle. In some embodiments, R¹⁵ is selected from C₃₋₁₂carbocycle, such as phenyl or cyclopentyl. In some embodiments, R¹⁵ isselected from

In some embodiments, R¹⁵ is —NR¹R².

In some embodiments, for a compound of Formula (III), R¹ is selectedfrom hydrogen and C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionallysubstituted with one or more R⁷. In some embodiments, R¹ is selectedfrom hydrogen and —CH₃.

In some embodiments, for a compound of Formula (III), R² is selectedfrom C₁₋₆ alkyl, C₃₋₁₂ carbocycle, 3- to 12-membered heterocycle andbenzyl, each of which is optionally substituted with one or moresubstituents independently selected from halogen, —CN, C₁₋₄ alkyl, C₁₋₃haloalkyl, —OH and —NH₂. In some embodiments, R² is benzyl, optionallysubstituted with one or more R⁷. In some embodiments, R² is benzyl,optionally substituted with one or more substituents independentlyselected from halogen, —CN, C₁₋₄ alkyl, C₁₋₃ haloalkyl, —OH and —NH₂. Insome embodiments, R² is C₁₋₆ alkyl or C₃₋₈ cycloalkyl, each of which isoptionally substituted with one or more substituents independentlyselected from halogen, —CN, C₁₋₃ haloalkyl, —OH, —NH₂, optionallysubstituted phenyl and optionally substituted pyridyl. In someembodiments, R² is C₃₋₈ cycloalkyl, such as cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl. In some embodiments, R² is C₁₋₄ alkyl, suchas methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl ortert-butyl. In some embodiments, R² is C₁₋₆ alkyl, C₃₋₈ cycloalkyl, orbenzyl, each of which is optionally substituted with one or moresubstituents independently selected from halogen, —CN, C₁₋₄ alkyl, C₁₋₃haloalkyl, —OH and —NH₂.

In some embodiments, for a compound of Formula (III), R¹⁵ is —NR¹R²,wherein R¹ and R² are taken together with the nitrogen atom to whichthey are attached to form a 3- to 12-membered heterocycle, optionallysubstituted with one or more R⁷, such as one or more substituentsindependently selected from halogen, —CN, C₁₋₄ alkyl, C₁₋₃ haloalkyl,—OH and —NH₂. In some embodiments, R¹ and R² are taken together with theatom to which they are attached to form an optionally substituted 3- to7-membered monocyclic heterocycloalkyl or an optionally substituted 5-to 12-membered fused bicyclic heterocycloalkyl. The 3- to 12-memberedheterocycle formed by R¹, R² and the nitrogen atom to which they areattached may be selected from

In some embodiments, a compound of Formula (III) is represented byFormula (III-A) or (III-B):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from C₁₋₆ alkyl and C₃₋₁₂ carbocycle, each of which isoptionally substituted with one or more R⁷;

R¹² is independently selected at each occurrence from R⁷; and

n is an integer from 0 to 3.

In some embodiments, for a compound of Formula (III-A) or (III-B), R¹¹is selected from C₁₋₆ alkyl and C₃₋₁₂ carbocycle, each of which isoptionally substituted with one or more R⁷; R¹² is independentlyselected at each occurrence from R⁷; and n is an integer from 0 to 3.

In some embodiments, for a compound of Formula (III-A) or (III-B), R¹¹is C₁₋₆ alkyl, such as C₁₋₄ alkyl. In some embodiments, R¹¹ is selectedfrom methyl, ethyl, iso-propyl and tert-butyl. In some embodiments, R¹¹is selected from C₁₋₄ alkyl and C₃₋₁₂ cycloalkyl, each of which isoptionally substituted with one or more R⁷. In some embodiments, R¹¹ is—CH₃. In some embodiments, R¹¹ is selected from R⁷.

In some embodiments, for a compound of Formula (III-A) or (III-B), R¹²is independently selected at each occurrence from halogen, —CN, alkoxy,haloalkoxy, alkyl and haloalkyl. In some embodiments, R¹² isindependently selected at each occurrence from halogen, —CN, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkyl and C₁₋₄ haloalkyl. In someembodiments, R¹² is independently selected at each occurrence fromhalogen, —CN, C₁₋₄ alkoxy, C₁₋₄ fluoroalkoxy, C₁₋₄ alkyl and C₁₋₄haloalkyl. In some embodiments, R¹² is independently selected at eachoccurrence from halogen, —CN, C₁₋₄ alkyl and C₁₋₃ haloalkyl. In someembodiments, R¹² is independently selected at each occurrence from —F,—CN, —CH₃ and —CF₃. In some embodiments, R¹² is independently selectedat each occurrence from halogen, —CN, —CH₃ and —CF₃.

In some embodiments, for a compound of Formula (III-A) or (III-B), n isan integer from 1 to 3, such as n is 1.

In some embodiments, for a compound of Formula (III-A) or (III-B):

R¹¹ is selected from C₁₋₆ alkyl, optionally substituted with one or moreR⁷;

R¹² is independently selected at each occurrence from halogen, —CN, C₁₋₄alkyl and C₁₋₃ haloalkyl; and

n is an integer from 1 to 3.

In some embodiments, for a compound of Formula (III-A) or (III-B):

R¹¹ is selected from C₁₋₆ alkyl and C₃₋₁₂ carbocycle, each of which isoptionally substituted with one or more R⁷;

R¹² is independently selected at each occurrence from halogen, —CN,alkoxy, haloalkoxy, alkyl and haloalkyl; and

n is an integer from 0 to 3.

In some embodiments, for a compound of Formula (III-A) or (III-B), oneof W¹ or W⁶ is S. In some embodiments, one of W¹ or W⁶ is S and W⁵ is C.In some embodiments, W⁶ and W⁵ are N and W¹ is CH. In some embodiments,W¹ is NH, W⁶ is CH, and W⁵ is C.

In some embodiments, a compound of Formula (III) is represented byFormula (III-C):

or a pharmaceutically acceptable salt thereof, wherein:

Z is selected from C₃₋₁₂ cycloalkyl and 3- to 12-memberedheterocycloalkyl, each of which is optionally substituted with one ormore R⁷.

In some embodiments, for a compound of Formula (III-C), Z is selectedfrom C₃₋₁₂ monocyclic cycloalkyl or C₅₋₁₂ fused bicyclic cycloalkyl,each of which is optionally substituted with one or more R⁷. In someembodiments, Z is C₅₋₁₂ fused bicyclic cycloalkyl, optionallysubstituted with one or more R⁷. In some embodiments, Z is selected fromC₃₋₁₂ monocyclic cycloalkyl or C₅₋₁₂ bicyclic cycloalkyl, each of whichis optionally substituted with one or more R⁷. In some embodiments, Z issubstituted with one or more substituents independently selected fromhalogen, —CN, C₁₋₄ alkyl and C₁₋₃ haloalkyl. In some embodiments, Z isselected from

In some embodiments, for a compound of Formula (III), (III-A), (III-B)or (III-C), R³ is C₂-alkynyl optionally substituted with one or more R⁷.In some embodiments, the C₂-alkynyl is selected from

In some embodiments, for a compound of Formula (III), (III-A), (III-B)or (III-C), R³ is —OR⁸. In some embodiments, R³ is selected from

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), one of W¹ or W⁶ is S. In some embodiments, one of W¹ or W⁶is S and W⁵ is C. In some embodiments, W⁶ and W⁵ are N and W¹ is CH. Insome embodiments, W¹ is NH, W⁶ is CH, and W⁵ is C.

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), R¹ is selected from hydrogen and C₁₋₆ alkyl, wherein theC₁₋₆ alkyl is optionally substituted with one or more R⁷. In someembodiments, R¹ is selected from hydrogen and —CH₃. In some embodiments,R¹ is C₁₋₆ alkyl, such as —CH₃.

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), W³ is N. In some embodiments, W² is N or CH, such as W² isN. In some embodiments, W¹ is N or CH, such as W¹ is N. In someembodiments, W¹ is CH. In some embodiments, W³ is N and W² and W¹ areindependently N or CH. In some embodiments, W¹ is CH, W² is N and W³ isN. In some embodiments, W¹ is N, W² is CH and W³ is N. In someembodiments, W¹, W² and W³ are each N. In some embodiments, W², W³, andW⁵ are each N. In some embodiments, W¹, W², and W³ are each N. In someembodiments, W² and W³ are each N and W¹ is S. In some embodiments, W²and W³ are each N and W⁶ is S. In some embodiments W², W³, W¹, W⁶ and W⁵are each N. In some embodiments, W⁵ is C. In some embodiments, W¹ is NH,W² is N, W³ is N, W⁴ is C, W⁵ is C and W⁶ is CH. In some embodiments, W¹is S, W² is N, W³ is N, W⁴ is C, W⁵ is C and W⁶ is CH. In someembodiments, W¹ is selected from N, NH, CR⁶ and S.

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), R³ is selected from hydrogen, halogen and cyano; and C₁₋₆alkyl, aryl, heteroaryl and benzyl, each of which is optionallysubstituted with one or more R⁷. In some embodiments, R³ is selectedfrom hydrogen, halogen, —CN, C₁₋₃ alkyl and C₁₋₃ haloalkyl. In someembodiments, R³ is selected from —H, —Cl and —CN. In some embodiments,R³ is selected from hydrogen, halogen and cyano.

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), R³ is selected from halogen and cyano; and C₁₋₆ alkyl, aryl,heteroaryl and benzyl, each of which is optionally substituted with oneor more R⁷. In some embodiments, R³ is selected from halogen, —CN, C₁₋₃alkyl and C₁₋₃ haloalkyl. In some embodiments, R³ is selected from —Cland —CN. In some embodiments, R³ is selected from halogen and cyano.

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), A is selected from —O—, —S—, —S(═O)—, —S(═O)₂— and—OP(O)(OH)—. In some embodiments, A is selected from —S(═O)— and—S(═O)₂. In some embodiments, A is selected from —S— and —S(═O)₂. Insome embodiments, A is selected from —S— and —S(═O)—. In someembodiments, A is —S—. In some embodiments, A is —S(═O)—. In someembodiments, A is —S(═O)₂. In some embodiments, A is selected from—OP(O)(OH)— and —O—. In some embodiments, A is —OP(O)(OH)—. In someembodiments, A is —O—. In some embodiments, A is selected from —O—, —S—,—S(═O)— and —S(═O)₂—.

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), at least one of R⁴ and R⁵ is C₁₋₆ alkyl, optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, —OR⁸, —S—S—R⁸, —S—C(O)R⁸, —OC(O)R⁸, —OC(O)OR⁸ and—P(O)(OR⁸)₂.

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), R⁴ and R⁵ are independently selected from C₁₋₆ alkyl,optionally substituted at each occurrence with one or more substituentsselected from halogen, —OR⁸, —S—S—R⁸, —S—C(O)R⁸, —OC(O)R⁸, —OC(O)OR⁸ and—P(O)(OR⁸)₂. In some embodiments, R⁴ and R⁵ are independently selectedfrom —CH₂OC(O)R⁸ and —CH₂OC(O)OR⁸. In some embodiments, R⁴ and R⁵ areindependently selected from —CH₂OC(O)C(CH₃)₃, —CH₂OC(O)OCH(CH₃)₂,—CH₂OC(O)CH₃, —CH₂CH₂—S—S—(CH₂)₂OH and —CH₂CH₂—S—C(O)CH₃.

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), R⁴ is phenyl, optionally substituted with —OR⁸; R⁵ is C₁₋₆alkyl substituted with one or more substituents selected from —OC(O)R⁸,—C(O)OR⁸, and —OC(O)OR⁸; and R⁸ is C₁₋₆ alkyl.

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), R⁴ is a 3- to 12-membered heterocycle. In some embodiments,R⁴ is a 6-membered heterocycle, such as pyridyl. In some embodiments R⁴is pyrimidyl. In some embodiments, R⁴ and R⁵ are taken together with theatoms to which they are attached to form a 3- to 12-memberedheterocycle, optionally substituted with one or more R⁷.

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), X and Y are each —O—. In some embodiments, one of X and Y is—O— and the other one of X and Y is —NR⁸—. In some embodiments, one of Xand Y is —O— and the other one of X and Y is —NR⁸, and R⁴ and R⁵ aretaken together with the atoms to which they are attached to form a 3- to12-membered heterocycle, such as a 6-membered heterocycle, optionallysubstituted with one or more R⁷.

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), R¹⁴ is selected from hydrogen; and C₃₋₁₂ carbocycle and 3-to 12-membered heterocycle each of which is optionally substituted withone or more substituents selected from halogen, —NO₂, —CN, —OR⁸, —SR⁸,—N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰,—NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —C(O)R⁸, —C(O)OR⁸,—OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸,—NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰,—P(O)(OR⁸)₂, —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl. In some embodiments, R¹⁴ is phenyl.

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), W¹ is selected from N and CR⁶; W² is selected from N and CH;W³ is N; R¹ is selected from hydrogen and C₁₋₄ alkyl; R³ is selectedfrom halogen and cyano; and R⁶ is selected from halogen, cyano and C₁₋₄alkyl.

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), —X—R⁴ and —Y—R⁵ are each —OH.

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), at least one of R⁴ and R⁵ is selected from C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸,—S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂,—NR⁸S(═O)₂NR⁹R¹⁰, —S—S—R⁸, —S—C(O)R⁸, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,—OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,—NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,—P(O)(R⁸)₂, —OP(O)(OR⁸)₂, ═O, ═S, ═N(R⁸); and C₃₋₁₂ carbocycle, and 3-to 12-membered heterocycle, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, C₁₋₆ alkyl, —OR⁸, —OC(O)R⁸, and —C(O)R⁸.

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), R⁴ and R⁵ are independently selected from C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸,—S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂,—NR⁸S(═O)₂NR⁹R¹⁰, —S—S—R⁸, —S—C(O)R⁸, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,—OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,—NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,—P(O)(R⁸)₂, —OP(O)(OR⁸)₂, ═O, ═S, ═N(R⁸); and C₃₋₁₂ carbocycle, and 3-to 12-membered heterocycle, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, C₁₋₆ alkyl, —OR⁸, —OC(O)R⁸, and —C(O)R⁸.

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), R⁴ and R⁵ are independently selected from C₁₋₆ alkylsubstituted with one or more substituents selected from halogen,—OC(O)R⁸, —OC(O)OR⁸, —S—S—R⁸, —S—C(O)R⁸, —OR⁸, and —P(O)(OR⁸)₂. In someembodiments, R⁴ and R⁵ are independently selected from hydrogen and C₁₋₆alkyl, wherein each C₁₋₆ alkyl is optionally substituted at eachoccurrence with one or more substituents selected from halogen,—OC(O)R⁸, —OC(O)OR⁸, —S—S—R⁸, —S—C(O)R⁸, —OR⁸, and —P(O)(OR⁸)₂. In someembodiments, R⁴ and R⁵ are independently selected from C₁₋₆ alkylsubstituted with one or more substituents selected from —OC(O)R⁸ and—OC(O)OR⁸. In some embodiments, R⁴ and R⁵ are independently selectedfrom C₁ alkyl substituted with one or more substituents selected from—OC(O)R⁸ and —OC(O)OR⁸, wherein R⁸ is C₁₋₆ alkyl. In some embodiments,R⁴ and R⁵ are independently selected from —CH₂OC(O)C(CH₃)₃,—CH₂OC(O)OCH(CH₃)₂, and —CH₂OC(O)CH₃. In some embodiments, R⁴ and R⁵ areeach —CH₂OC(O)C(CH₃)₃. In some embodiments, R⁴ and R⁵ are each—CH₂OC(O)OCH(CH₃)₂.

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), R⁴ and R⁵ are independently selected from C₁₋₆ alkylsubstituted with one or more substituents selected from —S—S—R⁸, and—S—C(O)R⁸. In some embodiments, R⁴ and R⁵ are independently selectedfrom —CH₂CH₂—S—S—(CH₂)₂OH and —CH₂CH₂—S—C(O)CH₃. In some embodiments, R⁴and R⁵ are each —CH₂CH₂—S—S—(CH₂)₂OH. In some embodiments, R⁴ and R⁵ areeach —CH₂CH₂—S—C(O)CH₃.

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), R⁴ and R⁵ are independently selected from C₃₋₁₂ carbocycle,such as phenyl, wherein the C₃₋₁₂ carbocycle is optionally substitutedwith one or more substituents selected from halogen, C₁₋₆ alkyl, —OR⁸,—OC(O)R⁸, —C(O)OR⁸, and —C(O)R⁸. In some embodiments, R⁴ and R⁵ areindependently selected from phenyl, wherein the phenyl is optionallysubstituted with —OR⁸, such as phenyl substituted with —OCH₂CH₃. In someembodiments, one of R⁴ and R⁵ is selected from C₃₋₁₂ carbocycle, such asphenyl and benzyl, and the other of R⁴ and R⁵ is selected from C₁₋₆alkyl substituted with one or more substituents selected from —OC(O)R⁸,—C(O)OR⁸, and —OC(O)OR⁸, wherein R⁸ is C₁₋₆ alkyl.

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), R⁴ and R⁵ are independently selected from hydrogen andC₁₋₆alkylene-OR²⁰, wherein R²⁰ at each occurrence is independentlyselected from C₇₋₂₀alkyl and C₇₋₂₀alkenyl. In some embodiments, one ofR⁴ or R⁵ is selected from —C₁₋₃alkylene-O—C₇₋₂₀alkyl and—C₁₋₃alkylene-O—C₇₋₂₀alkenyl, such as one of R⁴ or R⁵ is selected fromhexadecyloxypropyl (—CH₂(CH₂)₂O(CH₂)₁₅CH₃), octadecyloxyethyl(—CH₂CH₂O(CH₂)₁₇CH₃), oleyoxyethyl (—CH₂CH₂O(CH₂)₈CH═CH(CH₂)₇CH₃), andoleyoxypropyl (—CH₂(CH₂)₂O(CH₂)₈CH═CH(CH₂)₇CH₃), and the other of R⁴ andR⁵ is hydrogen.

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), R⁴ and R⁵ are taken together with the atoms to which theyare attached to form a heterocycle, optionally substituted with one ormore R⁷. In some embodiments, the heterocycle is a 5- or 6-memberedheterocycle. In some embodiments, R⁴ and R⁵ are taken together with theatoms to which they are attached to form a heterocycle selected from:

In some embodiments, R⁷ is a halogen.

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), X and Y are each —O—. In some embodiments, one of X and Y is—O— and the other one of X and Y is —N(R⁸)—. In some embodiments, atleast one of —X—R⁴ and —Y—R⁵ comprises an amino acid or an amino acidester, such as an L-alanine ester, e.g., —NHCH(CH₃)C(O)OCH(CH₃)₂ and—NHCH(CH₃)C(O)OCH₂CH₃. In some embodiments, at least one of —X—R⁴ and—Y—R⁵ comprises alanine, serine, phenylalanine, valine, or two or morethereof.

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), —X—R⁴ and —Y—R⁵ are independently selected from:

—OH, —O—CH₃, —O—CH₂CH₃, —O—CH₂-Ph, —O-Ph,

In some embodiments, —X—R⁴ and —Y—R⁵ are different, such as —X—R⁴ is —OHand —Y—R⁵ is —O(CH₂)₃O(CH₂)₁₅CH₃. In some embodiments, one of —X—R⁴ and—Y—R⁵ is —OH, and the other one of —X—R⁴ and —Y—R⁵ is selected from

In some embodiments, —X—R⁴ and —Y—R⁵ are selected from the samemoieties, for example, —X—R⁴ is

and —Y—R⁵ is

or —X—R⁴ is

and —Y—R⁵ is

In some embodiments, —X—R⁴ and —Y—R⁵ are each —O—CH₃, —O—CH₂CH₃,—O—CH₂Ph, —OPh,

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), —X—R⁴ is selected from: —OH, —OCH₃, —OCH₂CH₃, —OCH₂Ph, —OPh,

and —Y—R⁵ is selected from —OCH₃, —OCH₂CH₃, —OCH₂Ph, —OPh,

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), W¹ is selected from N and CR⁶; W² is selected from N and CH;W³ is N; W⁴ is C; W⁵ is N; W⁶ is CH; R¹ is selected from hydrogen andC₁₋₄ alkyl; R³ is selected from halogen and cyano; and R⁶ is selectedfrom hydrogen, halogen, cyano and C₁₋₄ alkyl.

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), W¹ is CH; W² is N; W³ is N; W⁴ is C; W⁵ is N; W⁶ is CH; R¹is hydrogen; R² is C₃₋₁₂ carbocycle; and R³ is selected from a)C₂-alkynyl optionally substituted with one or more R⁷; and b) —OR⁸.

In some embodiments, for a compound of Formula (III), (III-A), (III-B),or (III-C), —X—R⁴ and —Y—R⁵ are each —OH. In some embodiments, —X—R⁴ and—Y—R⁵ are each —OH and A is —OP(O)(OH)—.

In some embodiments, a compound or salt of Formula (I), (I-A), (I-B),(I-C), (II), (II-A), (II-B), (II-C), (III), (III-A), (III-B) or (III-C)may be a prodrug, e.g., wherein a phosphonic acid in the parent compoundis presented as an ester, or carboxylic acid present in the parentcompound is presented as an ester. The term “prodrug” is intended toencompass compounds which, under physiologic conditions, are convertedinto pharmaceutical agents, i.e., parent compound, of the presentdisclosure. One method for making a prodrug is to include one or moreselected moieties which are hydrolyzed under physiologic conditions toreveal the desired molecule. In other embodiments, the prodrug isconverted by an enzymatic activity of the host animal such as specifictarget cells in the host animal. For example, esters or carbonates(e.g., esters or carbonates of alcohols or carboxylic acids and estersof phosphonic acids) are preferred prodrugs of the present disclosure.

Phosphonic acids are typically ionized at physiological pH (6.5-7.4).Molecules containing this group may be highly charged, and thus may havepoor oral bioavailability due to poor cell permeability. Prodrugs mayovercome poor cell permeability of phosphonic acids to achieve oralbioavailability (see, e.g., Hecker and Erion, J. Med. Chem. 2008, 51,2328, incorporated herein by reference). One or more cleavable maskinggroup(s) may be attached to a phosphonic acid moiety to mask the chargeof the acid at physiological pH, improving the cell permeability andoral bioavailability of the molecule. Upon entering systemiccirculation, the masking group(s) are cleaved, releasing the phosphonicacid. Cleavable/masking groups include, but are not limited to:acyloxyalkyl diesters, alkyloxycarbonyloxyalkyl diesters, acyloxyalkylmonoesters, alkyloxycarbonyloxyalkyl monoesters, cyclic1-aryl-1,3-propanyl esters, phosphonic diamides, phosphonic monoamides,benzyl esters, aryl phosphonamidates, dioxolenones, S-acylthioethylesters, aryl esters, lipid esters, nitrofuranylmethyl amidates, andcyclosaligenyl prodrugs.

In some embodiments, a compound of Formula (I), (I-A), (I-B), (I-C),(II), (II-A), (II-B), (II-C), (III), (III-A), (III-B) or (III-C) isprovided as a substantially pure stereoisomer. The stereoisomer may beprovided in at least 90% diastereomeric excess. In some embodiments, acompound of Formula (I), (I-A), (I-B), (I-C), (II), (II-A), (II-B),(II-C), (III), (III-A), (III-B) or (III-C) may have an diastereomericexcess of at least about 80%, at least about 81%, at least about 82%, atleast about 83%, at least about 84%, at least about 85%, at least about86%, at least about 87%, at least about 88%, at least about 89%, atleast about 90%, at least about 91%, at least about 92%, at least about93%, at least about 94%, at least about 95%, at least about 96%, atleast about 97%, at least about 98%, or even higher. In someembodiments, a compound of Formula (I), (I-A), (I-B), (I-C), (II),(II-A), (II-B), (II-C), (III), (III-A), (III-B) or (III-C) may have andiastereomeric excess of about 80%, about 81%, about 82%, about 83%,about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%,about 97%, about 98% or about 99%.

The chemical entities described herein can be synthesized according toone or more illustrative schemes herein and/or techniques known in theart. Materials used herein are either commercially available or preparedby synthetic methods generally known in the art. These schemes are notlimited to the compounds listed in the examples or by any particularsubstituents, which are employed for illustrative purposes. Althoughvarious steps are described and depicted in Schemes 1-7, the steps insome cases may be performed in a different order than the order shown inSchemes 1-7. Various modifications to these synthetic reaction schemesmay be made and will be suggested to one skilled in the art havingreferred to the disclosure contained in this Application. Numberings orR groups in each scheme do not necessarily correspond to that of theclaims or other schemes or tables herein.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure, generally within a temperature range from−10° C. to 200° C. Further, except as otherwise specified, reactiontimes and conditions are intended to be approximate, e.g., taking placeat about atmospheric pressure within a temperature range of about −10°C. to about 110° C. over a period of about 1 to about 24 hours;reactions left to run overnight average a period of about 16 hours.

In some embodiments, compounds of the invention may be prepared by thefollowing reaction schemes:

In some embodiments, a compound of Formula 1-5 may be prepared accordingto steps outlined in Scheme 1. For example, reaction of compound 1-1with amine 1-2 (e.g., wherein R¹ and R² are alkyl or substituted alkyl)can provide intermediate 1-3. The reaction may be carried out in asuitable organic solvent in the presence of a base. Suitable bases forthe reaction include, but are not limited to, organic bases, forexample, triethylamine, N,N-diisopropylethylamine,1,4-diazabicyclo[2.2.2]octane, and inorganic bases, for example, cesiumbicarbonate, sodium carbonate, and potassium carbonate. Compound 1-3 maybe alkylated with a suitable alkylation reagent to give compound 1-4.Elevated temperature may be needed for the alkylation to occur. Thetemperature may be in a range of 50° C. to 100° C. Further substitutionand hydrolysis of compound 1-4 can be carried out to afford phosphonicacid 1-5.

Alternatively, a compound of Formula 2-4 may be prepared according tosteps outlined in Scheme 2. Alkylation of compound 2-1 with a suitablealkylation reagent can provide phosphonate 2-2. At this stage, amine 1-2may be introduced to give compound 2-3. Elevated temperature may beneeded for the alkylation to occur. The temperature may be in a range of80° C. to 120° C. Further substitution and hydrolysis of compound 2-3can be carried out to afford compound 2-4.

In some embodiments, a compound of Formula 3-8 may be prepared accordingto steps outlined in Scheme 3. For example, reaction of compound 3-1with amine 3-2 (e.g., wherein R¹ and R² are independently alkyl orsubstituted alkyl) can provide intermediate 3-3. The reaction may becarried out in a suitable organic solvent in the presence of a base.Suitable bases for the reaction include, but are not limited to, organicbases, such as triethylamine, N,N-diisopropylethylamine,1,4-diazabicyclo[2.2.2]octane, and inorganic bases, such as cesiumbicarbonate, sodium carbonate, and potassium carbonate. Alcohol 3-3 maybe reacted with a suitable sulfonyl chloride to give compound 3-4. Thesulfur atom of the linker may be introduced by reacting compound 3-4with reagent 3-5 in the presence of a base, such as sodium ethoxide, togive thioether 3-6. Oxidation of thioether 3-6 with an oxidationreagent, such as oxone, affords sulfone 3-7. Further substitution andhydrolysis of compound 3-7 can be carried out to afford compound 3-8.

Alternatively, a compound of Formula 4-6 may be prepared according tosteps outlined in Scheme 4. Thioacetate 4-1 may be prepared fromcompound 4-3 under standard Mitsuobu conditions or by displacing asulfonate intermediate, e.g., compound 4-4, with potassium thioacetate.Alkylation of compound 4-1 with bromide 4-2 in the presence of a base,such as sodium isopropoxide, can provide phosphonate 4-6.

In some embodiments, a compound of Formula 5-5 may be prepared by thesteps outlined in Scheme 5. For example, reaction of 5-1 withP,P′-methylenebis-phosphonic dichloride in the presence of a suitablebase can provide intermediate 5-2. Reaction of intermediate 5-2 withamine 5-3 in the presence of base generates intermediate 5-4.Deprotection of 5-4 using strong acid, such as formic acid, yieldscompound 5-5.

In some embodiments, a compound of Formula 6-8 may be prepared by thesteps outlined in Scheme 6. For example, treatment of 6-1 with ammoniumsulfate followed by acetic anhydride and TMSOTf in the presence of(2S,3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetateyields intermediate 6-2. Treatment of 6-2 in the presence of base withamine 6-3 can then yield intermediate 6-4. Subsequent protection of 6-4with 2,2-dimethoxy propane under acidic conditions can yieldintermediate 6-5. Treatment of 6-5 with1-(diethoxyphosphorylmethylsulfonyl)-4-methyl-benzene in the presence ofa strong base, such as magnesium tertbutoxide, then can produceintermediate 6-6. Deprotection of the phosphonate hydroxyls of 6-6 usingbromotrimethysilane can produce intermediate 6-7. Finally, deprotectionof the ribose hydroxyls in strong acid, such as formic acid, can yieldcompound 6-8.

In some embodiments, a compound of Formula 7-10 may be prepared by thesteps outlined in Scheme 7. Iodination of 7-1 can yield intermediate7-2. Reaction of intermediate 7-2 with amine 7-3 in the presence of basecan yield intermediate 7-4. Deprotection of 7-4 with TBAF can yieldintermediate 7-5. Treatment of 7-5 with1-(diethoxyphosphorylmethylsulfonyl)-4-methyl-benzene in the presence ofa strong base, such as magnesium tert-butoxide, can yield compound 7-6.Treatment of 7-6 under Sonogashira coupling conditions with alkyne 7-7can then yield intermediate 7-8. Deprotection of the phosphonatehydroxyls of 7-8 with bromotrimethylsilane can produce intermediate 7-9.Finally, deprotection with a strong acid, such as formic acid, yieldscompound 7-10.

In some embodiments, a compound of the present invention, for example acompound of a formula given in Table 1, is synthesized according to oneof the general routes outlined in Schemes 1-7, Examples 1-22 or bymethods generally known in the art.

TABLE 1 No. Structure m/z IUPAC Name  1

[M + H]⁺: 450; [M − H]⁻: 452 [(2R,3S,4R,5R)-5-[6-(benzylamino)purin-9-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid  2

[M + H]⁺: 362; [M − H]⁻: 360 [(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxy- tetrahydrofuran-2- yl]methoxymethylphosphonic acid 3

[M − H]⁻: 484 [(2R,3S,4R,5R)-5-[6- (benzylamino)-2-chloro-purin-9-yl]-3,4-dihydroxy- tetrahydrofuran-2- yl]methoxymethylphosphonic acid  4

[M − H]⁻: 475 [(2R,3S,4R,5R)-5-[6- (benzylamino)-2-cyano-purin-9-yl]-3,4-dihydroxy- tetrahydrofuran-2- yl]methoxymethylphosphonic acid  5

[M + H]⁺: 481; [M − H]⁻: 479 [(2R,3S,4R,5R)-5-[6- (benzylamino)-2-(methylamino)purin-9-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid  6

[M + H]⁺: 496; [M − H]⁻: 494 6-(benzylamino)-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5- (phosphonomethoxymeth-yl)tetrahydrofuran-2-yl]purine-2- carboxylic acid  7

[M + H]⁺: 480; [M − H]⁻: 478 [(2R,3S,4R,5R)-5-[6-(benzylamino)purin-9-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methoxymethyl-ethoxy- phosphinic acid  8

[M − H]⁻: 526 [(2R,3S,4R,5R)-5-[6- (benzylamino)-2-phenyl-purin-9-yl]-3,4-dihydroxy- tetrahydrofuran-2- yl]methoxymethylphosphonic acid  9

[M + H]⁺: 532; [M − H]⁻: 530 [(2R,3S,4R,5R)-5-[6- (benzylamino)-2-(1-methylpyrazo1-4-yl)purin-9-yl]- 3,4-dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid  10

[M + H]⁺: 518; [M − H]⁻: 516 [(2R,3S,4R,5R)-5-[6-(benzylamino)-2-(1H-pyrazol-4- yl)purin-9-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  11

[M + H]⁺: 376; [M − H]⁻: 374 [(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(methylamino)purin-9- yl]tetrahydrofuran-2-yl]methoxymethylphosphonic acid  12

[M + H]⁺: 404; [M − H]⁻: 402 [(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(isopropylamino)purin-9- yl]tetrahydrofuran-2-yl]methoxymethylphosphonic acid  13

[M + H]⁺: 406; [M − H]⁻: 404 [(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(2-hydroxyethylamino)purin-9- yl]tetrahydrofuran-2-yl]methoxymethylphosphonic acid  14

[(3aR,4R,6R,6aR)-4-[2-chloro-6- (isopropylamino)purin-9-yl]-2,2-dimethyl-3a,4,6,6a- tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxymethylphosphonic acid  15

[M + H]⁺: 438; [M − H]⁻: 436 [(2R,3S,4R,5R)-5-[2-chloro-6-(isopropylamino)purin-9-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid  16

[M + H]⁺: 429; [M − H]⁻: 427 [(2R,3S,4R,5R)-5-[2-cyano-6-(isopropylamino)purin-9-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid  17

[M + H]⁺: 390; [M − H]⁻: 388 [(2R,3S,4R,5R)-5-[6-(ethylamino)purin-9-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid  18

[M + H]⁺: 466; [M − H]⁻: 464 [(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(1-phenylethylamino)purin-9- yl]tetrahydrofuran-2-yl]methoxymethylphosphonic acid  19

[M + H]⁺: 453; [M − H]⁻: 451 [(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(2-pyridylmethylamino)purin- 9-yl]tetrahydrofuran-2-yl]methoxymethylphosphonic acid  20

[M + H]⁺: 500; [M − H]⁻: 498 [(2R,3S,4R,5R)-5-[2-chloro-6- [[(1R)-1-phenylethyl]amino]purin-9-yl]- 3,4-dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid  21

[M + H]⁺: 500; [M − H]⁻: 498 [(2R,3S,4R,5R)-5-[2-chloro-6-[[(1S)-1-phenylethyl]amino]purin- 9-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  22

[M + H]⁺: 542; [M − H]⁻: 540 [(2R,3S,4R,5R)-5-[2-benzyl-6-(benzylamino)purin-9-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid  23

[M + H]⁺: 478; [M − H]⁻: 476 [(2R,3S,4R,5R)-3,4-dihydroxy-5- [6-[(1-phenylcyclopropyl)amino]purin- 9-yl]tetrahydrofuran-2-yl]methoxymethylphosphonic acid  24

[M + H]⁺: 402; [M − H]⁻: 400 [(2R,3S,4R,5R)-5-[6-(cyclopropylamino)purin-9-yl]- 3,4-dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid  25

[M + H]⁺: 405; [M − H]⁻: 403 [(2R,3S,4R,5R)-5-[6-(2-aminoethylamino)purin-9-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid  26

[M + H]⁺: 420; [M − H]⁻: 418 [(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(3-hydroxypropylamino)purin- 9-yl]tetrahydrofuran-2-yl]methoxymethylphosphonic acid  27

[M + H]⁺: 453; [M − H]⁻: 451 [(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(3-pyridylmethylamino)purin- 9-yl]tetrahydrofuran-2-yl]methoxymethylphosphonic acid  28

[M − H]⁻: 451 [(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(4-pyridylmethylamino)purin- 9-yl]tetrahydrofuran-2-yl]methoxymethylphosphonic acid  29

[M + H]⁺: 466; [M − H]⁻: 464 [(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(2-phenylethylamino)purin-9- yl]tetrahydrofuran-2-yl]methoxymethylphosphonic acid  30

[M + H]⁺: 438; [M − H]⁻: 436 [(2R,3S,4R,5R)-5-(6-anilinopurin-9-yl)-3,4-dihydroxy- tetrahydrofuran-2- yl]methoxymethylphosphonic acid 31

[M + H]⁺: 418; [M − H]⁻: 416 [(2R,3S,4R,5R)-3,4-dihydroxy-5- [6-[isopropyl(methyl)amino]purin-9- yl]tetrahydrofuran-2-yl]methoxymethylphosphonic acid  32

[M + H]⁺: 430; [M − H]⁻: 428 [(2R,3S,4R,5R)-5-[6-(cyclopentylamino)purin-9-yl]- 3,4-dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid  33

[M + H]⁺: 418; [M − H]⁻: 416 [(2R,3S,4R,5R)-5-[6-(tert-butylamino)purin-9-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid  34

[M + H]⁺: 416; [M − H]⁻: 414 [(2R,3S,4R,5R)-5-[6-(cyclobutylamino)purin-9-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid  35

[M + H]⁺: 444; [M − H]⁻: 442 [(2R,3S,4R,5R)-5-[6-(cyclohexylamino)purin-9-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid  36

[M + H]⁺: 491; [M − H]⁻: 489 [(2R,3S,4R,5R)-5-[2-cyano-6-[[(1S)-1-phenylethyl]amino]purin- 9-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  37

[(2R,3S,4R,5R)-3,4-dihydroxy-5- ([1,2,4]triazolo[3,4-f]purin-7-yl)tetrahydrofuran-2- yl]methoxymethylphosphonic acid  38

[(2R,3S,4R,5R)-3,4-dihydroxy-5- imidazo[2,1-f]purin-3-yl-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  39

[M + H]⁺: 492; [M − H]⁻: 490 [(2R,3S,4R,5R)-5-[6-(benzylamino)-2-cyclopropyl- purin-9-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  40

[M + H]⁺: 430; [M − H]⁻: 428 [(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(isopropylamino)-2-vinyl- purin-9-yl]tetrahydrofuran-2-yl]methoxymethylphosphonic acid  41

[M − H]⁻: 430 [(2R,3S,4R,5R)-5-[2-ethyl-6-(isopropylamino)purin-9-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid  42

[(2R,3S,4R,5R)-5-(1-benzyl-6- oxo-purin-9-yl)-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  43

[M + H]⁺: 416; [M − H]⁻: 414 [(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-pyrrolidin-1-ylpurin-9- yl)tetrahydrofuran-2-yl]methoxymethylphosphonic acid  44

[M + H]⁺: 405; [M − H]⁻: 403 [(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-isopropoxypurin-9- yl)tetrahydrofuran-2- yl]methoxymethylphosphonicacid  45

[M + H]⁺: 492; [M − H]⁻: 490 [(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(2-phenylpyrrolidin-1-yl)purin- 9-yl]tetrahydrofuran-2-yl]methoxymethylphosphonic acid  46

[M + H]⁺: 423; [M − H]⁻: 421 [(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-phenylpurin-9- yl)tetrahydrofuran-2- yl]methoxymethylphosphonic acid 47

[M + H]⁺: 372; [M − H]⁻: 370 [(2R,3S,4R,5R)-5-(6-cyanopurin-9-yl)-3,4-dihydroxy- tetrahydrofuran-2- yl]methoxymethylphosphonic acid 48

[M − H]⁻: 361 [(2R,3S,4R,5R)-3,4-dihydroxy-5- (6-hydroxypurin-9-yl)tetrahydrofuran-2- yl]methoxymethylphosphonic acid  49

[M + H]⁺: 484; [M − H]⁻: 482 [(2R,3S,4R,5R)-5-[6-[[(1S)-1-(4-fluorophenyl)ethyl]amino]purin- 9-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid  50

[M + H]⁺: 484; [M − H]⁻: 482 [(2R,3S,4R,5R)-5-[6-[[(1S)-1-(3-fluorophenyl)ethyl]amino]purin- 9-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid  51

[M + H]⁺: 484; [M − H]⁻: 482 [(2R,3S,4R,5R)-5-[6-[[(1S)-1-(2-fluorophenyl)ethyl]amino]purin- 9-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid  52

[M + H]⁺: 478; [M − H]⁻: 476 [(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(indan-1-ylamino)purin-9- yl]tetrahydrofuran-2-yl]methoxymethylphosphonic acid  53

[M + H]⁺: 441; [M − H]⁻: 439 [(2R,3S,4R,5R)-5-[6-(2-fluorophenyl)purin-9-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid  54

[M + H]⁺: 498; [M − H]⁻: 496 [(2R,3S,4R,5R)-5-(2-chloro-6-isoindolin-2-yl-purin-9-yl)-3,4- dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid  55

[M + H]⁺: 431; [M − H]⁻: 429 [(2R,3S,4R,5R)-5-[6-(cyclopentoxy)purin-9-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid  56

[M + H]⁺: 485; [M − H]⁻: 483 [(2R,3S,4R,5R)-5-[4-(benzylamino)-2-chloro- pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  57

[M + H]⁺: 485; [M − H]⁻: 483 [(2R,3S,4R,5R)-5-[7-(benzylamino)-5-chloro- imidazo[4,5-b]pyridin-3-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  58

[M + H]⁺: 477; [M − H]⁻: 475 [(2R,3S,4R,5R)-5-[6-[(3-cyanophenyl)methylamino]purin- 9-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid  59

[M + H]⁺: 531; [M − H]⁻: 529 [(2R,3S,4R,5R)-3,4-dihydroxy-5- [6-[(4-sulfamoylphenyl)meth- ylamino]purin- 9-yl]tetrahydrofuran-2-yl]methoxymethylphosphonic acid  60

[M + H]⁺: 499; [M − H]⁻: 497 [(2R,3S,4R,5R)-5-[2-chloro-4- [[(1S)-1-phenylethyl]amino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  61

[M + H]⁺: 499; [M − H]⁻: 497 [(2R,3S,4R,5R)-5-[2-chloro-4- [[(1R)-1-phenylethyl]amino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  62

[M + H]⁺: 490; [M − H]⁻: 488 [(2R,3S,4R,5R)-5-[2-cyano-4- [[(1R)-1-phenylethyl]amino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  63

[M − H]⁻: 529 [(2R,3S,4R,5R)-3,4-dihydroxy-5- [6-[(3-sulfamoylphenyl)meth- ylamino]purin- 9-yl]tetrahydrofuran-2-yl]methoxymethylphosphonic acid  64

[M + H]⁺: 482 [(2R,3S,4R,5R)-3,4-dihydroxy-5- [6-[[3-(hydroxymethyl)phenyl]meth- ylamino]purin- 9-yl]tetrahydrofuran-2-yl]methoxymethylphosphonic acid  65

[M + H]⁺: 495; [M − H]⁻: 493 [(2R,3S,4R,5R)-5-[6-[(3-carbamoylphenyl)meth- ylamino]purin- 9-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  66

[M + H]⁺: 530; [M − H]⁻: 528 [(2R,3S,4R,5R)-3,4-dihydroxy-5- [6-[(3-methylsulfonylphenyl)meth- ylamino]purin- 9-yl]tetrahydrofuran-2-yl]methoxymethylphosphonic acid  67

[M − H]⁻: 488 [(2R,3S,4R,5R)-5-[2-cyano-4- [[(1S)-1-phenylethyl]amino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  68

[M + H]⁺: 517; [M − H]⁻: 515 [(2R,3S,4R,5R)-5-[2-chloro-4- [[(1S)-1-(4-fluorophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  69

[M + H]⁺: 517; [M − H]⁻: 515 [(2R,3S,4R,5R)-5-[2-chloro-4- [[(1R)-1-(4-fluorophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  70

[M + H]⁺: 463; [M − H]⁻: 461 [(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  71

[M + H]⁺: 454; [M − H]⁻: 452 [(2R,3S,4R,5R)-5-[2-cyano-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  72

[M − H]⁻: 506 [(2R,3S,4R,5R)-5-[2-cyano-4- [[(1S)-1-(4-fluorophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  73

[M + H]⁺: 508; [M − H]⁻: 506 [(2R,3S,4R,5R)-5-[2-cyano-4- [[(1R)-1-(4-fluorophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  74

[M − H]⁻: 515 [(2R,3S,4R,5R)-5-[2-chloro-4- [[(1S)-1-(3-fluorophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  75

[M − H]⁻: 506 [(2R,3S,4R,5R)-5-[2-cyano-4- [[(1S)-1-(3-fluorophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  76

[M + H]⁺: 517; [M − H]⁻: 515 [(2R,3S,4R,5R)-5-[2-chloro-5-fluoro-4-[[(1S)-1- phenylethyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid  77

[M + H]⁺: 513; [M − H]⁻: 511 [(2R,3S,4R,5R)-5-[2-chloro-4- [[(1R)-1-phenylpropyl]amino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  78

[M + H]⁺: 527; [M − H]⁻: 525 [(2R,3S,4R,5R)-5-[2-chloro-4-[[(1R)-2-methyl-1-phenyl- propyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid  79

[M + H]⁺: 517; [M − H]⁻: 515 [(2R,3S,4R,5R)-5-[2-chloro-4- [[(1S)-1-(2-fluorophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  80

[M + H]⁺: 508; [M − H]⁻: 506 [(2R,3S,4R,5R)-5-[2-cyano-4- [[(1S)-1-(2-fluorophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  81

[M − H]⁻: 506 [(2R,3S,4R,5R)-5-[2-cyano-4- [[(1R)-1-(3-fluorophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  82

[M + H]⁺: 517; [M − H]⁻: 515 [(2R,3S,4R,5R)-5-[2-chloro-4- [[(1R)-1-(3-fluorophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  83

[M + H]⁺: 485; [M − H]⁻: 483 [(2R,3S,4R,5R)-5-[2-chloro-4- [(3,3-difluorocyclobutyl)a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  84

[M − H]⁻: 511 [(2R,3S,4R,5R)-5-[2-chloro-4- [[(1S)-1-phenylpropyl]amino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  85

[M − H]⁻: 525 [(2R,3S,4R,5R)-5-[2-chloro-4- [[(1S)-2-methyl-1-phenyl-propyl]amino]pyrrolo[2,3- d]pyrirnidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  86

[M − H]⁻: 393 [(2R,3S,4R,5R)-5-(4-amino-2-chloro-pyrrolo[2,3-d]pyrimidin-7- yl)-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid  87

[M − H]⁻: 515 [(2R,3S,4R,5R)-5-[2-chloro-4- [[(1R)-1-(2-fluorophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  88

[M + H]⁺: 508; [M − H]⁻: 506 [(2R,3S,4R,5R)-5-[2-cyano-4- [[(1R)-1-(2-fluorophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  89

[M − H]⁻: 522 [(2R,3S,4R,5R)-5-[2-chloro-4- [[(1R)-1-(4-cyanophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  90

[M + H]⁺: 513 [(2R,3S,4R,5R)-5-[2-chloro-4- [[(1S)-1-(p-tolyl)ethyl]amino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  91

[M + H]⁺: 504; [M − H]⁻: 502 [(2R,3S,4R,5R)-5-[2-cyano-4- [[(1S)-1-(p-tolyl)ethyl]amino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  92

[M + H]⁺: 437 [(2R,3S,4R,5R)-5-[2-chloro-4- (isopropylamino)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid  93

[M + H]⁺: 423; [M − H]⁻: 421 [(2R,3S,4R,5R)-5-[2-chloro-4-(dimethylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  94

[M − H]⁻: 531 [(2R,3S,4R,5R)-5-[2-chloro-4- [[(1R)-1-(4-chlorophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  95

[M − H]⁻: 513 [(2R,3S,4R,5R)-5-[2-cyano-4- [[(1R)-1-(4-cyanophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid  96

[M − H]⁻: 407 [(2R,3S,4R,5R)-5-[2-chloro-4- (methylamino)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid  97

[M + H]⁺: 428 [(2R,3S,4R,5R)-5-[2-cyano-4- (isopropylamino)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid  98

[M + H]⁺: 423 [(2R,3S,4R,5R)-5-[2-chloro-4- (ethylamino)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid  99

[M − H]⁻: 477 [(2R,3S,4R,5R)-5-[2-chloro-4- (tetrahydropyran-4-ylamino)pyrrolo[2,3-d]pyrimidin- 7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 100

[M + H]⁺: 465; [M − H]⁻: 463 [(2R,3S,4R,5R)-5-(2-chloro-4-morpholino-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 101

[M + H]⁺: 499; [M − H]⁻: 497 [(2R,3S,4R,5R)-5-[2-chloro-4- [(3,3-difluorocyclopentyl)a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 102

[M + H]⁺: 475; [M − H]⁻: 473 [(2R,3S,4R,5R)-5-[4-(3-bicyclo[3.1.0]hexanylamino)-2- chloro-pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2- yl]methoxymethylphosphonic acid103

[M + H]⁺: 489; [M − H]⁻: 487 [(2R,3S,4R,5R)-5-[4-(3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrol-2-yl)-2-chloro-pyrrolo[2,3-d]pyrimidin-7- yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 104

[M + H]⁺: 514; [M − H]⁻: 512 [(2R,3S,4R,5R)-5-[2-chloro-6-[methyl-[(1R)-1- phenylethyl]amino]purin-9-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 105

[M + H]⁺: 461; [M − H]⁻: 459 [(2R,3S,4R,5R)-5-[4-(3-azabicyclo[3.1.0]hexan-3-yl)-2- chloro-pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2- yl]methoxymethylphosphonic acid106

[M − H]⁻: 565 [(2R,3S,4R,5R)-5-[2-chloro-4- [[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]a- mino]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 107

[M − H]⁻: 412 [(2R,3S,4R,5R)-5-[2-cyano-4- (dimethylamino)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 108

[M − H]⁻: 412 [(2R,3S,4R,5R)-5-[2-cyano-4- (ethylamino)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 109

[M + H]⁺: 449; [M − H]⁻: 447 [(2R,3S,4R,5R)-5-[2-chloro-4-(cyclobutylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 110

[M + H]⁺: 440; [M − H]⁻: 438 [(2R,3S,4R,5R)-5-[2-cyano-4-(cyclobutylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 111

[M − H]⁻: 475 [(2R,3S,4R,5R)-5-[2-chloro-4-(cyclohexylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 112

[M + H]⁺: 435; [M − H]⁻: 433 [(2R,3S,4R,5R)-5-[4-(azetidin-1-yl)-2-chloro-pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 113

[M + H]⁺: 505; [M − H]⁻: 503 [(2R,3S,4R,5R)-5-[2-cyano-6-[methyl-[(1R)-1- phenylethyl]amino]purin-9-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 114

[M + H]⁺: 567; [M − H]⁻: 565 [(2R,3S,4R,5R)-5-[2-chloro-4- [[(1R)-1-[4-(trifluoromethyl)phenyl]ethyl]a- mino]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 115

[M + H]⁺: 558; [M − H]⁻: 556 [(2R,3S,4R,5R)-5-[2-cyano-4- [[(1R)-1-[4-(trifluoromethyl)phenyl]ethyl]a- mino]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 116

[M + H]⁺: 535; [M − H]⁻: 533 [(2R,3S,4R,5R)-5-[2-chloro-4-[[(1S)-1-(2,4- difluorophenyl)ethyl]a- mino]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid 117

[M + H]⁺: 524; [M − H]⁻: 522 [(2R,3S,4R,5R)-5-[2-chloro-4- [[(1S)-1-(4-cyanophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 118

[M + H]⁺: 400; [M − H]⁻: 398 [(2R,3S,4R,5R)-5-[2-cyano-4-(methylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 119

[M + H]⁺: 468; [M − H]⁻: 466 [(2R,3S,4R,5R)-5-[2-cyano-4-(cyclohexylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 120

[M + H]⁺: 470; [M − H]⁻: 468 [(2R,3S,4R,5R)-5-[2-cyano-4-(tetrahydropyran-4- ylamino)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2- yl]methoxymethylphosphonic acid121

[M + H]⁺: 513 [(2R,3S,4R,5R)-5-[2-chloro-4- [(4,4- difluorocyclohexyl)a-mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid 122

[M − H]⁻: 424 [(2R,3S,4R,5R)-5-[4-(azetidin-1- yl)-2-cyano-pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 123

[M − H]⁻: 483 [(2R,3S,4R,5R)-5-[2-chloro-4- (3,3-difluoropyrrolidin-1-yl)pyrrolo[2,3-d]pyrimidin-7-yl]- 3,4-dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid 124

[M + H]⁺: 513; [M − H]⁻: 511 [(2R,3S,4R,5R)-5-[2-chloro-4-[methyl-[(1R)-1- phenylethyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 125

[M + H]⁺: 476; [M − H]⁻: 474 [(2R,3S,4R,5R)-5-[2-cyano-4-(3,3-difluoropyrrolidin-1- yl)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 126

[M + H]⁺: 463; [M − H]⁻: 461 [(2R,3S,4R,5R)-5-[2-chloro-4-(1-piperidyl)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 127

[M + H]⁺: 456; [M − H]⁻: 454 [(2R,3S,4R,5R)-5-(2-cyano-4-morpholino-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 128

[M − H]⁻: 497 [(2R,3S,4R,5R)-5-[2-chloro-4- (4,4-difluoro-1-piperidyl)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 129

[M + H]⁺: 490 [(2R,3S,4R,5R)-5-[2-cyano-4- (4,4-difluoro-1-piperidyl)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 130

[M + H]⁺: 517; [M − H]⁻: 515 [(2R,3S,4R,5R)-5-[2-chloro-5-fluoro-4-[[(1R)-1- phenylethyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 131

[M + H]⁺: 513; [M − H]⁻: 511 [(2R,3S,4R,5R)-5-[2-chloro-4-[methyl-[(1S)-1- phenylethyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 132

[M + H]⁺: 627; [M − H]⁻: 625 [(2R,3S,4R,5R)-5-[2-chloro-4-[methyl-[(1R)-1- phenylethyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethyl-(2,2- dimethylpropanoyloxymeth- oxy)phosphinic acid 133

[M + H]⁺: 741 [[(2R,3S,4R,5R)-5-[2-chloro-4- [methyl-[(1R)-1-phenylethyl]amino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl-(2,2- dimethylpropanoyloxymeth-oxy)phosphoryl]oxymethyl 2,2- dimethylpropanoate 134

[M + H]⁺: 498; [M − H]⁻: 496 [(2R,3S,4R,5R)-5-[6-chloro-4- [[(1R)-1-phenylethyl]amino]pyrrolo[2,3- b]pyridin-1-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 135

[M − H]⁻: 516 [(2R,3S,4R,5R)-5-[2-chloro-4- [[(1R)-1-(5-fluoro-2-pyridyl)ethyl]amino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 136

[M + H]⁺: 513; [M − H]⁻: 511 [(2R,3S,4R,5R)-5-[2-chloro-4- [[(1R)-1-(p-tolyl)ethyl]amino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 137

[M − H]⁻: 502 [(2R,3S,4R,5R)-5-[2-cyano-4- [[(1R)-1-(p-tolyl)ethyl]amino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 138

[M − H]⁻: 524 [(2R,3S,4R,5R)-5-[2-cyano-4- [[(1S)-1-(2,4-difluorophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 139

[M + H]⁺: 518; [M − H]⁻: 516 [(2R,3S,4R,5R)-5-[2-chloro-4-[[(1S)-1-(5-fluoro-2- pyridyl)ethyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 140

[M + H]⁺: 533; [M − H]⁻: 531 [(2R,3S,4R,5R)-5-[2-chloro-4- [[(1S)-1-(4-chlorophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 141

[M − H]⁻: 513 [(2R,3S,4R,5R)-5-[2-cyano-4- [[(1S)-1-(4-cyanophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 142

[M + H]⁺: 504; [M − H]⁻: 502 [(2R,3S,4R,5R)-5-[2-cyano-4- [(4,4-difluorocyclohexyl)a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 143

[M + H]⁺: 454; [M − H]⁻: 452 [(2R,3S,4R,5R)-5-[2-cyano-4-(1-piperidyl)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 144

[M + H]⁺: 535; [M − H]⁻: 533 [(2R,3S,4R,5R)-5-[2-chloro-4-[[(1R)-1-(2,4- difluorophenyl)ethyl]a- mino]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid 145

[M − H]⁻: 507 [(2R,3S,4R,5R)-5-[2-cyano-4- [[(1R)-1-(5-fluoro-2-pyridyl)ethyl]amino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 146

[M + H]⁺: 509; [M − H]⁻: 507 [(2R,3S,4R,5R)-5-[2-cyano-4-[[(1S)-1-(5-fluoro-2- pyridyl)ethyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 147

[M − H]⁻: 556 [(2R,3S,4R,5R)-5-[2-cyano-4- [[(1S)-1-[4-(trifluoromethyl)phen- yl]ethyl]amino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 148

[M + H]⁺: 500 [(2S,3S,4R,5R)-5-[6- (benzylamino)purin-9-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid149

[M + H]⁺: 544; [M − H]⁻: 542 [[(2S,3S,5R)-5-[6-(benzylamino)purin-9-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methylsulfanyl-phenyl- methyl]phosphonic acid 150

[M + H]⁺: 576; [M − H]⁻: 574 [R2S,3S,5R)-5-[6-(benzylamino)purin-9-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methylsulfonyl-phenyl- methyl]phosphonic acid 151

[M + H]⁺: 468; [M − H]⁻: 466 [(2S,3S,5R)-5-[6-(benzylamino)purin-9-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methylsulfanylmeth- ylphosphonic acid 152

[M − H]⁻: 546 [(2S,3S,4R,5R)-5-[2-chloro-6-[[(1S)-1-phenylethyl]amino]purin- 9-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid 153

[M − H]⁻: 545 [(2S,3S,4R,5R)-5-[2-chloro-4- [[(1S)-1-phenylethyl]amino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid 154

[M + H]⁺: 547; [M − H]⁻: 545 [(2S,3S,4R,5R)-5-[2-chloro-4- [[(1R)-1-phenylethyl]amino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid 155

[M + H]⁺: 511; [M − H]⁻: 509 [(2S,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid 156

[M + H]⁺: 537; [M − H]⁻: 535 [(2S,3S,4R,5R)-5-[4-(3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrol-2-yl)-2-chloro-pyrrolo[2,3-d]pyrimidin-7- yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methylsulfonylmeth- ylphosphonic acid 157

[M + H]⁺: 561; [M − H]⁻: 559 [(2S,3S,4R,5R)-5-[2-chloro-4-[methyl-[(1R)-1- phenylethyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methylsulfonylmeth- ylphosphonic acid 158

[M + H]⁺: 526; [M − H]⁻: 526 [(2S,3S,4R,5R)-5-[4-(3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrol-2-yl)-2-cyano-pyrrolo[2,3-d]pyrimidin-7- yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methylsulfonylmeth- ylphosphonic acid 159

[M + H]⁺: 523; [M − H]⁻: 521 [(2S,3S,4R,5R)-5-[4-(3-bicyclo[3.1.0]hexanylamino)-2- chloro-pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2- yl]methylsulfonylmeth-ylphosphonic acid 160

[M + H]⁺: 553; [M − H]⁻: 551 [(2S,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmethyl- isopropoxy-phosphinic acid161

[M + H]⁺: 625; [M − H]⁻: 623 [(2S,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmethyl-(2,2-dimethylpropanoyloxymeth- oxy)phosphinic acid 162

[M − H]⁻: 483 [(2S,3S,4R,5R)-5-[2-chloro-4- (isopropylamino)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methylsulfonylmeth- ylphosphonic acid 163

[M + H]⁺: 497; [M − H]⁻: 495 [(2S,3S,4R,5R)-5-(2-chloro-4-pyrrolidin-1-yl-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid 164

[M − H]⁻: 531 [(2S,3S,4R,5R)-5-[2-chloro-4- (3,3-difluoropyrrolidin-1-yl)pyrrolo[2,3-d]pyrimidin-7-yl]- 3,4-dihydroxy-tetrahydrofuran-2-yl]methylsulfonylmeth- ylphosphonic acid 165

[M + H]⁺: 739 [[(2S,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmethyl-(2,2-dimethylpropanoyloxymeth- oxy)phosphoryl]oxymethyl 2,2-dimethylpropanoate 166

[M + H]⁺: 723 [R2S,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfinylmethyl-(2,2-dimethylpropanoyloxymeth- oxy)phosphoryl]oxymethyl 2,2-dimethylpropanoate 167

[M + H]⁺: 565; [M − H]⁻: 563 [(2S,3S,4R,5R)-5-[2-chloro-4- [[(1R)-1-(4-fluorophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid168

[M − H]⁻: 563 [(2S,3S,4R,5R)-5-[2-chloro-4- [[(1R)-1-(2-fluorophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid169

[M − H]⁻: 559 [(2S,3S,4R,5R)-5-[2-chloro-4- [[(1R)-1-(p-tolyl)ethyl]amino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid 170

[M + H]⁺: 561; [M − H]⁻: 559 [(2S,3S,4R,5R)-5-[2-chloro-4- [[(1S)-1-(p-tolyl)ethyl]amino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid 171

[M − H]⁻: 545 [(2S,3S,4R,5R)-5-[2-chloro-4- [(3,3-difluorocyclopentyl)a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid172

[M − H]⁻: 495 [(2S,3S,4R,5R)-5-[2-chloro-4-(cyclobutylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid 173

[M − H]⁻: 531 [(2S,3S,4R,5R)-5-[2-chloro-4- [(3,3- difluorocyclobutyl)a-mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methylsulfonylmeth- ylphosphonic acid 174

[M + H]⁺: 525; [M − H]⁻: 523 [(2S,3S,4R,5R)-5-[2-chloro-4-(cyclohexylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid 175

[M − H]⁻: 507 [(2S,3S,4R,5R)-5-[4-(3- azabicyclo[3.1.0]hexan-3-yl)-2-chloro-pyrrolo[2,3-d]pyrimidin-7- yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methylsulfonylmeth- ylphosphonic acid 176

[M − H]⁻: 469 [(2S,3S,4R,5R)-5-[2-chloro-4- (ethylamino)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methylsulfonylmeth- ylphosphonic acid 177

[M + H]⁺: 499; [M − H]⁻: 497 [(2S,3S,4R,5R)-5-[2-chloro-4-[isopropyl(methyl)a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid178

[M − H]⁻: 581 [(2S,3S,4R,5R)-5-[2-chloro-4- [[(1R)-1-(2,4-difluorophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid179

[M − H]⁻: 581 [(2S,3S,4R,5R)-5-[2-chloro-4- [[(1R)-1-(4-chlorophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid180

[M + H]⁺: 572; [M − H]⁻: 570 [(2S,3S,4R,5R)-5-[2-chloro-4- [[(1R)-1-(3-cyanophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid181

[M + H]⁺: 572; [M − H]⁻: 570 [(2S,3S,4R,5R)-5-[2-chloro-4- [[(1S)-1-(4-cyanophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid182

[M + H]⁺: 561; [M − H]⁻: 559 [(2S,3S,4R,5R)-5-[2-chloro-4- [(4,4-difluorocyclohexyl)a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid183

[M + H]⁺: 583; [M − H]⁻: 581 [(2S,3S,4R,5R)-5-[2-chloro-4-[[(1S)-1-(2,4- difluorophenyl)ethyl]a- mino]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methylsulfonylmeth- ylphosphonic acid 184

[M + H]⁺: 491; [M − H]⁻: 489 [(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl-ethoxy- phosphinic acid 185

[M + H]⁺: 519; [M − H]⁻: 517 (2R,3R,4S,5R)-2-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-5-(diethoxyphosphorylmeth- oxymethyl)tetrahydrofuran- 3,4-diol 186

[M + H]⁺: 478; [M − H]⁻: 476 [(2R,3S,4R,5R)-5-[2-chloro-6-[cyclopentyl(methyl)amino]purin- 9-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 187

[M + H]⁺: 691; [M − H]⁻: 689 [[(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl-(2,2- dimethylpropanoyloxymeth-oxy)phosphoryl]oxymethyl 2,2- dimethylpropanoate 188

[M + H]⁺: 577; [M − H]⁻: 575 [(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl-(2,2- dimethylpropanoyloxymeth-oxy)phosphinic acid 189

[M + H]⁺: 535; [M − H]⁻: 533 [(2R,3S,4R,5R)-5-[2-cyano-4- [[(1R)-1-(2,4-difluorophenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 190

[M + H]⁺: 449; [M − H]⁻: 447 [(2R,3S,4R,5R)-5-(2-chloro-4-pyrrolidin-1-yl-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 191

[M − H]⁻: 486 [(2R,3S,4R,5R)-5-(2-chloro-4-cyclopentylsulfanyl-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 192

[M + H]⁺: 477; [M − H]⁻: 475 [(2R,3S,4R,5R)-5-[2-chloro-4-[cyclopentyl(methyl)a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 193

[M + H]⁺: 579; [M − H]⁻: 577 [(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl- (isopropoxycarbonyloxymeth-oxy)phosphinic acid 194

[M + H]⁺: 563; [M − H]⁻: 561 [(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl-(2- methylpropanoyloxymeth-oxy)phosphinic acid 195

[M − H]⁻: 489 [(2R,3S,4R,5R)-5-[2-chloro-4- [cyclopentyl(ethyl)a-mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid 196

[M + H]⁺: 517; [M − H]⁻: 515 [(2R,3S,4R,5R)-5-[2-chloro-4-[cyclopentyl(cyclopropylmethyl)a- mino]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2- yl]methoxymethylphosphonic acid197

[M − H]⁻: 537 [(2R,3S,4R,5R)-5-[2-chloro-4- [[(1R)-1-(4-cyclopropylphenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 198

[M − H]⁻: 537 [(2R,3S,4R,5R)-5-[2-chloro-4- [[(1S)-1-(4-cyclopropylphenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 199

[M − H]⁻: 475 [(2R,3S,4R,5R)-5-[2-chloro-4- (cyclopentylamino)-5-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid 200

[M − H]⁻: 475 [(2R,3S,4R,5R)-5-[2-chloro-4- (cyclopentylamino)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid 201

[M + H]⁺: 480; [M − H]⁻: 478 [(2R,3S,4R,5R)-5-[4-(3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrol-2-yl)-2-cyano-pyrrolo[2,3-d]pyrimidin-7- yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 202

[M + H]⁺: 551; [M − H]⁻: 549 [(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl- (methoxycarbonyloxymeth-oxy)phosphinic acid 203

[M + H]⁺: 717 [[(2R,3S,4R,5R)-5-[4- (3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-2- chloro-pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2- yl]methoxymethyl-(2,2-dimethylpropanoyloxymeth- oxy)phosphoryl]oxymethyl 2,2-dimethylpropanoate 204

[M − H]⁻: 528 [(2R,3S,4R,5R)-5-[2-cyano-4- [[(1S)-1-(4-cyclopropylphenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 205

[M − H]⁻: 528 [(2R,3S,4R,5R)-5-[2-cyano-4- [[(1R)-1-(4-cyclopropylphenyl)ethyl]a- mino]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 206

[M − H]⁻: 470 [(2R,3S,4R,5R)-5-(2-chloro-4-phenoxy-pyrrolo[2,3-d]pyrimidin- 7-yl)-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 207

[M − H]⁻: 486 [(2R,3S,4R,5R)-5-(2-chloro-4- phenylsulfanyl-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 208

[M + H]⁺: 721 [[(2R,3S,4R,5R)-5-[4- (3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-2- chloro-pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2- yl]methoxymethyl-(isopropoxycarbonyloxymeth- oxy)phosphoryl]oxymethyl isopropyl carbonate209

[M + H]⁺: 488; [M − H]⁻: 486 [(2R,3S,4R,5R)-5-[2-chloro-5- cyano-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 210

[M − H]⁻: 477 [(2R,3S,4R,5R)-5-[2,5-dicyano-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 211

[M − H]⁻: 469 [(2R,3S,4R,5R)-5-(4-anilino-2-chloro-pyrrolo[2,3-d]pyrimidin-7- yl)-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 212

[M − H]⁻: 454 [(2R,3S,4R,5R)-5-(2-chloro-4-phenyl-pyrrolo[2,3-d]pyrimidin-7- yl)-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 213

[M − H]⁻: 446 [(2R,3S,4R,5R)-5-(2-chloro-4- cyclopentyl-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 214

[M + H]⁺: 695; [M − H]⁻: 693 [[(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl- (isopropoxycarbonyloxymeth-oxy)phosphoryl]oxymethyl isopropyl carbonate 215

[M + H]⁺: 615; [M − H]⁻: 613 (2R,3R,4S,5R)-2-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-5-(diphenoxyphosphorylmeth- oxymethyl)tetrahydrofuran-3,4- diol 216

[M + H]⁺: 514; [M − H]⁻: 512 [(2R,3R,4R,5R)-5-[2-chloro-6- [[(1R)-1-phenylethyl]amino]purin-9-yl]- 3,4-dihydroxy-4-methyl-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 217

[M + H]⁺: 515; [M − H]⁻: 513 [(2R,3S,4R,5R)-5-[2-chloro-4-[[(1S)-2-hydroxy-1-phenyl- ethyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 218

[M + H]⁺: 515; [M − H]⁻: 513 [(2R,3S,4R,5R)-5-[2-chloro-4-[[(1R)-2-hydroxy-1-phenyl- ethyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 219

[M + H]⁺: 464; [M − H]⁻: 462 [(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentoxy)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 220

[M + H]⁺: 661 ethyl (2S)-2-[[[(2R,3S,4R,5R)-5- [2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl-[[(1S)-2- ethoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]a- mino]propanoate 221

[M + H]⁺: 539; [M − H]⁻: 537 [(2R,3S,4R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl-phenoxy- phosphinic acid 222

[M + H]⁺: 547; [M − H]⁻: 545 [(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl-(3-methyl-2- oxo-butoxy)phosphinicacid 223

[M + H]⁺: 561; [M − H]⁻: 559 [(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl-(3,3-dimethyl-2-oxo-butoxy)phosphinic acid 224

[M + H]⁺: 505; [M − H]⁻: 503 [(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl-isopropoxy- phosphinic acid 225

[M + H]⁺: 575; [M − H]⁻: 573 [(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl-[(5-methyl-2- oxo-1,3-dioxo1-4-yl)methoxy]phosphinic acid 226

[M + H]⁺: 627; [M − H]⁻: 625 (2R,3S,4R,5R)-2-[bis(2,2,2-trifluoroethoxy)phosphorylmeth- oxymethyl]-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]tetrahydrofuran-3,4-diol 227

[M + H]⁺: 651; [M − H]⁻: 649 (2R,3S,4R,5R)-2-[bis(4-fluorophenoxy)phosphorylmeth- oxymethyl]-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]tetrahydrofuran-3,4-diol 228

[M + H]⁺: 557; [M − H]⁻: 555 [(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl-(4- fluorophenoxy)phosphinic acid229

[M + H]⁺: 527; [M − H]⁻: 525 [[(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxy- hydroxy- phosphoryl]methylphosphonic acid230

[M − H]⁻: 553 [(2R,3S,4R,5R)-5-[4- (cyclopentylamino)-2-iodo-pyrrolo[2,3-d]pyrimidin-7-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid 231

[M + H]⁺: 497; [M − H]⁻: 495 [(2R,3S,4R,5R)-5-[4- (cyclopentylamino)-2-(trifluoromethyl)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 232

[M + H]⁺: 545; [M − H]⁻: 543 [(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl-(2,2,2- trifluoroethoxy)phosphinicacid 233

[M + H]⁺: 540; [M − H]⁻: 538 [(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl-(3- pyridyloxy)phosphinic acid 234

[M + H]⁺: 548; [M − H]⁻: 546 [(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl-[2- (dimethylamino)-2-oxo-ethoxy]phosphinic acid 235

[M + H]⁺: 534; [M − H]⁻: 532 [(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl-[2- (dimethylamino)ethoxy]phosphinicacid 236

[M + H]⁺: 633 2-[[(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl-[2- (dimethylamino)-2-oxo-ethoxy]phosphoryl]oxy-N,N- dimethyl-acetamide 237

[M + H]⁺: 606; [M − H]⁻: 604 [(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl-(morpholine-4-carbonyloxymethoxy)phosphinic acid 238

[M + H]⁺: 749; [M − H]⁻: 747 [[(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl-(morpholine-4-carbonyloxymethoxy)phos- phoryl]oxymethyl morpholine-4- carboxylate 239

[M + H]⁺: 479; [M − H]⁻: 477 [(2R,3S,4R,5R)-5-[4- (cyclopentylamino)-2-(difluoromethyl)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 240

[M − H]⁻: 462 [(2R,3S,4R,5R)-5-[6-chloro-4-(cyclopentylamino)pyrazolo[3,4- d]pyrimidin-1-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 241

[M + H]⁺: 464; [M − H]⁻: 462 [(2R,3S,4R,5R)-5-[2-chloro-4-[[(3R)-pyrrolidin-3- yl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 242

[M + H]⁺: 464; [M − H]⁻: 462 [(2R,3S,4R,5R)-5-[2-chloro-4-[[(3S)-pyrrolidin-3- yl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 243

[M + H]⁺: 483; [M − H]⁻: 481 [(2R,3S,4R,5R)-5-[4-(cyclopentylamino)-2-(3- hydroxyprop-1-ynyl)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 244

[M + H]⁺: 453; [M − H]⁻: 451 [(2R,3S,4R,5R)-5-[4-(cyclopentylamino)-2-ethynyl- pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 245

[M + H]⁺: 450 [(2R,3S,4R,5R)-5-[4-(azetidin-3-ylamino)-2-chloro-pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 246

[M + H]⁺: 745 [(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl-(3- hexadecoxypropoxy)phosphinicacid 247

[M + H]⁺: 459; [M − H]⁻: 457 [(2R,3S,4R,5R)-5-[4-(cyclopentylamino)-2-methoxy- pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 248

[M + H]⁺: 522; [M − H]⁻: 520 [(2R,3S,4R,5R)-5-[4-(cyclopentylamino)-2-(3- pyridyloxy)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 249

[M + H]⁺: 686 phenyl (2S)-2-[[[(2R,3S,4R,5R)- 5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl-phenoxy- phosphoryl]amino]propanoate250

[M + H]⁺: 445 [(2R,3S,4R,5R)-5-[4- (cyclopentylamino)-2-hydroxy-pyrrolo[2,3-d]pyrimidin-7-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid 251

[M + H]⁺: 663; [M − H]⁻: 661 [[(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl-(2- methylpropanoyloxymeth-oxy)phosphoryl]oxymethyl 2- methylpropanoate 252

[M + H]⁺: 497 [(2R,3S,4R,5R)-5-[4- (cyclopentylamino)-2-(3-methoxyprop-1-ynyl)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 253

[M + H]⁺: 495 [(2R,3S,4R,5R)-5-[4- (cyclopentylamino)-2-(3-methylbut-1-ynyl)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 254

[M + H]⁺: 509 [(2R,3S,4R,5R)-5-[4- (cyclopentylamino)-2-(3,3-dimethylbut-1-ynyl)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 255

[M + H]⁺: 493 [(2R,3S,4R,5R)-5-[4- (cyclopentylamino)-2-(2-cyclopropylethynyl)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 256

[M + H]⁺: 498 [(2R,3S,4R,5R)-5-[4- (cyclopentylamino)-2-[(3S)-3-hydroxybut-1-ynyl]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 257

[M + H]⁺: 489; [M − H]⁻: 487 [(2R,3S,4R,5R)-5-[4-(cyclopentylamino)-2-(2- hydroxyethoxy)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 258

[M + H]⁺: 503; [M − H]⁻: 501 [(2R,3S,4R,5R)-5-[4-(cyclopentylamino)-2-(3- hydroxypropoxy)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 259

[M + H]⁺: 516 [(2R,3S,4R,5R)-5-[4- (cyclopentylamino)-2-[2- (dimethyla-mino)ethoxy]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 260

[M + H]⁺: 503; [M − H]⁻: 501 [(2R,3S,4R,5R)-5-[4-(cyclopentylamino)-2-(2- methoxyethoxy)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 261

[M + H]⁺: 503; [M − H]⁻: 501 [(2R,3S,4R,5R)-5-[4-(cyclopentylamino)-2-[(2R)-2- hydroxypropoxy]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 262

[M + H]⁺: 473; [M − H]⁻: 471 [(2R,3S,4R,5R)-5-[4-(cyclopentylamino)-2-ethoxy- pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 263

[M + H]⁺: 503; [M − H]⁻: 501 [(2R,3S,4R,5R)-5-[4-(cyclopentylamino)-2-(2- hydroxypropoxy)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 264

[M + H]⁺: 536; [M − H]⁻: 534 [(2R,3S,4R,5R)-5-[4-(cyclopentylamino)-2-(2- pyridylmethoxy)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 265

[M − H]⁻: 516 [(2R,3S,4R,5R)-5-[6-chloro-4- [[(1S)-1-(4-fluorophenyl)ethyl]a- mino]pyrazolo[3,4- d]pyrimidin-1-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 266

[M + H]⁺: 467 [(2R,3S,4R,5R)-5-[4- (cyclopentylamino)-2-prop-1-ynyl-pyrrolo[2,3-d]pyrimidin-7- yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 267

[M + H]⁺: 497 [(2R,3S,4R,5R)-5-[4- (cyclopentylamino)-2-[(3R)-3-hydroxybut-1-ynyl]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 268

[[(2R,3S,4R,5R)-5-[2-chloro-4- (cyclopentylamino)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethyl-[[3-(2- methoxyethoxy)-2,2-dimethyl- propanoyl]oxymeth-oxy]phosphoryl]oxymethyl 3-(2- methoxyethoxy)-2,2-dimethyl- propanoate269

[M − H]⁻: 516 [(2R,3S,4R,5R)-5-[6-chloro-4- [[(1R)-1-(4-fluorophenyl)ethyl]a- mino]pyrazolo[3,4- d]pyrimidin-1-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 270

[M − H]⁻: 448 [(2R,3S,4R,5R)-5-[6-chloro-4-(cyclobutylamino)pyrazolo[3,4- d]pyrimidin-1-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 271

[M − H]⁻: 484 [(2R,3S,4R,5R)-5-[6-chloro-4- [(3,3- difluorocyclobutyl)a-mino]pyrazolo[3,4- d]pyrimidin-1-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonic acid 272

[M + H]⁺: 511; [M − H]⁻: 509 [(2R,3S,4R,5R)-5-[4-(cyclopentylamino)-2-(3-hydroxy- 3-methyl-but-1-ynyl)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 273

[M + H]⁺: 651; [M − H]⁻: 649 [(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl-[[3-(2- methoxyethoxy)-2,2-dimethyl-propanoyl]oxymethoxy]phosphinic acid 274

[M − H]⁻: 488 [(2R,3S,4R,5R)-5-[4- (3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-6- chloro-pyrazolo[3,4-d]pyrimidin-1-yl]-3,4-dihydroxy- tetrahydrofuran-2- yl]methoxymethylphosphonic acid275

[M − H]⁻: 484 [(2R,3S,4R,5R)-5-[6-chloro-4- (3,3-difluoropyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-1- yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 276

[M − H]⁻: 508 [(2R,3S,4R,5R)-5-[4- (cyclopentylamino)-2-[2-(1-hydroxycyclo- propyl)ethynyl]pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 277

[M + H]⁺: 692 [[(2R,3S,4R,5R)-5-[6-chloro-4-(cyclopentylamino)pyrazolo[3,4- d]pyrimidin-1-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl-(2,2- dimethylpropanoyloxymeth-oxy)phosphoryl]oxymethyl 2,2- dimethylpropanoate 278

[M − H]⁻: 576 [(2R,3S,4R,5R)-5-[6-chloro-4-(cyclopentylamino)pyrazolo[3,4- d]pyrimidin-1-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethyl-(2,2- dimethylpropanoyloxymeth-oxy)phosphinic acid 279

[M − H]⁻: 474 [(2R,3S,4R,5R)-5-[4-(3- bicyclo[3.1.0]hexanylamino)-6-chloro-pyrazolo[3,4-d]pyrimidin- 1-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 280

[M − H]⁻: 460 [(2R,3S,4R,5R)-5-[4-(3- azabicyclo[3.1.0]hexan-3-yl)-6-chloro-pyrazolo[3,4-d]pyrimidin- 1-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 281

[M + H]⁺: 564 (2R,3R,4S,5R)-2-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-5-[(8-methyl-2-oxo-1,4-dihydro-3,1,2$l{circumflex over ( )}{5}- benzoxazaphosphinin-2-yl)methoxymethyl]tetrahydrofuran- 3,4-diol 282

[[(2R,3S,4R,5R)-5-[2-chloro-6- (cyclopentylamino)purin-9-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxy-hydroxy-phosphoryl]methylphosphonic acid 283

[M + H]⁺: 479; [M − H]⁻: 477 [(2R,3S,4R,5R)-5-[2-chloro-4- [(2R)-2-(hydroxymethyl)pyrrolidin-1- yl]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 284

[M + H]⁺: 463; [M − H]⁻: 461 [(2R,3S,4R,5R)-5-[2-chloro-4-[(2S)-2-methylpyrrolidin-1- yl]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 285

[M + H]⁺: 489 [(2R,3S,4R,5S)-5-[4- (3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-2- chloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 286

[M + H]⁺: 743 [[(2S,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmethyl- (isopropoxycarbonyloxymeth-oxy)phosphoryl]oxymethyl isopropyl carbonate 287

[M + H]⁺: 512; [M − H]⁻: 510 [(2S,3S,4R,5R)-5-[6-chloro-4-(cyclopentylamino)pyrazolo[3,4- d]pyrimidin-1-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid 288

[M − H]⁻: 499 [(2S,3S,4R,5R)-5-[4-(3- azabicyclo[3.1.0]hexan-3-yl)-6-cyano-pyrazolo[3,4-d]pyrimidin- 1-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methylsulfonylmeth- ylphosphonic acid 289

[M − H]⁻: 525 [(2S,3S,4R,5R)-5-[4- (cyclopentylamino)-2-(difluoromethyl)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid 290

[M − H]⁻: 446 [(2R,3S,4R,5R)-5-(2-chloro-4- pyrrolidin-1-yl-thieno[3,4-d]pyrimidin-7-yl)-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 291

[M − H]⁻: 555 [(2S,3S,4R,5R)-5-[6-cyano-4- [[(1R)-1-(4-fluorophenyl)ethyl]a- mino]pyrazolo[3,4- d]pyrimidin-1-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid292

[M − H]⁻: 523 [(2S,3S,4R,5R)-5-[6-cyano-4- [(3,3- difluorocyclobutyl)a-mino]pyrazolo[3,4- d]pyrimidin-1-yl]-3,4- dihydroxy-tetrahydrofuran-2-yl]methylsulfonylmeth- ylphosphonic acid 293

[M − H]⁻: 523 [(2S,3S,4R,5R)-5-[6-cyano-4- (3,3-difluoropyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-1- yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methylsulfonylmeth- ylphosphonic acid 294

[M + H]⁺: 489; [M − H]⁻: 487 [(2R,3S,4R,5R)-5-[4-(3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrol-2-yl)-2-chloro-5H-pyrrolo[3,2- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 295

[M + H]⁺: 506; [M − H]⁻: 504 [(2R,3S,4R,5S)-5-[4-(3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrol-2-yl)-2-chloro-thieno[3,2-d]pyrimidin-7- yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 296

[M + H]⁺: 503; [M − H]⁻: 501 [(2S,3S,4R,5R)-5-[6-cyano-4-(cyclopentylamino)pyrazolo[3,4- d]pyrimidin-1-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid 297

[M + H]⁺: 586 [(2R,3S,4R,5S)-5-[4- (3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-6- bromo-2-chloro-thieno[3,2-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methoxymethylphosphonic acid 298

[M − H]⁻: 461 [(2R,3S,4R,5S)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,1- f][1,2,4]triazin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 299

[M − H]⁻: 527 [(2S,3S,4R,5R)-5-[4- (3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-6- cyano-pyrazolo[3,4-d]pyrimidin-1-yl]-3,4-dihydroxy- tetrahydrofuran-2- yl]methylsulfonylmeth-ylphosphonic acid 300

[M − H]⁻: 513 [(2S,3S,4R,5R)-5-[4-(3- bicyclo[3.1.0]hexanylamino)-6-cyano-pyrazolo[3,4-d]pyrimidin- 1-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methylsulfonylmeth- ylphosphonic acid 301

[M + H]⁺: 627; [M − H]⁻: 625 [(2S,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmethyl- (isopropoxycarbonyloxymeth-oxy)phosphinic acid 302

[M − H]⁻: 446 [(2R,3S,4R,5R)-3,4-dihydroxy-5-(2-hydroxy-4-pyrrolidin-1-yl- thieno[3,4-d]pyrimidin-7-yl)tetrahydrofuran-2- yl]methoxymethylphosphonic acid 303

[M + H]⁺: 545 [(2S,3S,4R,5R)-5-[4- (cyclopentylamino)-2-(trifluoromethyl)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid 304

[M + H]⁺: 506 [(2R,3S,4R,5R)-5-[4- (3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-2- chloro-thieno[3,2-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2- yl]methoxymethylphosphonic acid305

[M + H]⁺: 480 [(2R,3S,4R,5S)-5-[2-chloro-4-(cyclopentylamino)thieno[3,2- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methoxymethylphosphonic acid 306

[M + H]⁺: 711 [[(2S,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3- d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmethyl-(2- methylpropanoyloxymeth-oxy)phosphoryl]oxymethyl 2- methylpropanoate 307

[M − H]⁻: 555 [(2S,3S,4R,5R)-5-[6-cyano-4- [[(1S)-1-(4-fluorophenyl)ethyl]a- mino]pyrazolo[3,4- d]pyrimidin-1-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid308

[M − H]⁻: 487 [(2S,3S,4R,5R)-5-[6-cyano-4-(cyclobutylamino)pyrazolo[3,4- d]pyrimidin-1-yl]-3,4-dihydroxy-tetrahydrofuran-2- yl]methylsulfonylmeth- ylphosphonic acid

Method of Use: In one aspect, the present invention provides a methodfor treating a proliferative disorder in a subject in need thereof,comprising administering to said subject a CD73 inhibitor. In someembodiments, the proliferative disorder is a cancer condition. In somefurther embodiments, said cancer condition is a cancer selected from thegroup consisting of leukemia, bladder cancer, glioma, glioblastoma, lungcancer, ovarian cancer, melanoma, prostate cancer, thyroid cancer,esophageal cancer, non-small cell lung cancer and breast cancer.

In a further embodiment, the present invention provides a method oftreating a cancer condition, wherein the CD73 inhibitor is effective inone or more of inhibiting proliferation of cancer cells, inhibitingmetastasis of cancer cells, reducing severity or incidence of symptomsassociated with the presence of cancer cells, promoting an immuneresponse to tumor cells, and suppressing hydrolysis of adenosinemonophosphate into adensosine. In some embodiments, said methodcomprises administering to the cancer cells a therapeutically effectiveamount of a CD73 inhibitor. In some embodiments, the administrationtakes place in vitro. In other embodiments, the administration takesplace in vivo.

As used herein, a therapeutically effective amount of a CD73 inhibitorrefers to an amount sufficient to effect the intended application,including but not limited to, disease treatment, as defined herein. Alsocontemplated in the subject methods is the use of a sub-therapeuticamount of a CD73 inhibitor for treating an intended disease condition.

The amount of the CD73 inhibitor administered may vary depending uponthe intended application (in vitro or in vivo), or the subject anddisease condition being treated, e.g., the weight and age of thesubject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art.

Measuring inhibition of biological effects of CD73 can compriseperforming an assay on a biological sample, such as a sample from asubject. Any of a variety of samples may be selected, depending on theassay. Examples of samples include, but are not limited to blood samples(e.g. blood plasma or serum), exhaled breath condensate samples,bronchoalveolar lavage fluid, sputum samples, urine samples, and tissuesamples.

A subject being treated with a CD73 inhibitor may be monitored todetermine the effectiveness of treatment, and the treatment regimen maybe adjusted based on the subject's physiological response to treatment.For example, if inhibition of a biological effect of CD73 inhibition isabove or below a threshold, the dosing amount or frequency may bedecreased or increased, respectively. The methods can further comprisecontinuing the therapy if the therapy is determined to be efficacious.The methods can comprise maintaining, tapering, reducing, or stoppingthe administered amount of a compound in the therapy if the therapy isdetermined to be efficacious. The methods can comprise increasing theadministered amount of a compound in the therapy if it is determined notto be efficacious. Alternatively, the methods can comprise stoppingtherapy if it is determined not to be efficacious. In some embodiments,treatment with a CD73 inhibitor is discontinued if inhibition of thebiological effect is above or below a threshold, such as in a lack ofresponse or an adverse reaction. The biological effect may be a changein any of a variety of physiological indicators.

In general, a CD73 inhibitor is a compound that inhibits one or morebiological effects of CD73. Examples of biological effects of CD73include, but are not limited to, production of adenosine and suppressionof T cell activation. Such biological effects may be inhibited by aboutor more than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, ormore.

In some other embodiments, the subject methods are useful for treating adisease condition associated with CD73. Any disease condition thatresults directly or indirectly from an abnormal activity or expressionlevel of CD73 can be an intended disease condition. In some embodiments,the disease condition is a proliferative disorder, such as describedherein, including but not limited to cancer. A role of CD73 intumorigenesis and tumor progression has been implicated in many humancancers. Constitutive activation of CD73 is emerging as a common themein diverse human cancers, consequently agents that target CD73 havetherapeutic value.

The data presented in the Examples herein below demonstrate theanti-cancer effects of a CD73 inhibitor. As such, the subject method isparticularly useful for treating a proliferative disorder, such as aneoplastic condition. Non-limiting examples of such conditions includebut are not limited to acanthoma, acinic cell carcinoma, acousticneuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilicleukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia,acute monocytic leukemia, acute myeloblastic leukemia with maturation,acute myeloid dendritic cell leukemia, acute myeloid leukemia, acutepromyelocytic leukemia, adamantinoma, adenocarcinoma, adenoid cysticcarcinoma, adenoma, adenomatoid odontogenic tumor, adrenocorticalcarcinoma, adult T-cell leukemia, aggressive NK-cell leukemia,AIDS-related cancers, AIDS-related lymphoma, alveolar soft part sarcoma,ameloblastic fibroma, anal cancer, anaplastic large cell lymphoma,anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma,angiomyolipoma, angiosarcoma, appendix cancer, astrocytoma, atypicalteratoid rhabdoid tumor, basal cell carcinoma, basal-like carcinoma,B-cell leukemia, B-cell lymphoma, bellini duct carcinoma, biliary tractcancer, bladder cancer, blastoma, bone cancer, bone tumor, brain stemglioma, brain tumor, breast cancer, brenner tumor, bronchial tumor,bronchioloalveolar carcinoma, brown tumor, Burkitt's lymphoma, carcinoidtumor, carcinoma, carcinosarcoma, Castleman's disease, central nervoussystem embryonal tumor, cerebellar astrocytoma, cerebral astrocytoma,cervical cancer, cholangiocarcinoma, chondroma, chondrosarcoma,chordoma, choriocarcinoma, choroid plexus papilloma, chronic lymphocyticleukemia, chronic monocytic leukemia, chronic myelogenous leukemia,chronic myeloproliferative disorder, chronic neutrophilic leukemia,clear cell renal cell carcinoma, clear-cell tumor, colon cancer,colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma,dermatofibrosarcoma protuberans, dermoid cyst, desmoplastic small roundcell tumor, diffuse large B cell lymphoma, dysembryoplasticneuroepithelial tumor, embryonal carcinoma, endodermal sinus tumor,endometrial cancer, endometrial uterine cancer, endometrioid tumor,enteropathy-associated T-cell lymphoma, ependymoblastoma, ependymoma,epithelioid sarcoma, erythroleukemia, esophageal cancer,esthesioneuroblastoma, Ewing's sarcoma, extracranial germ cell tumor,extragonadal germ cell tumor, extrahepatic bile duct cancer,extramammary Paget's disease, fallopian tube cancer, fibroma,fibrosarcoma, follicular lymphoma, follicular thyroid cancer,gallbladder cancer, ganglioglioma, ganglioneuroma, gastric cancer,gastric lymphoma, gastrointestinal cancer, gastrointestinal carcinoidtumor, gastrointestinal stromal tumor, germ cell tumor, germinoma,gestational choriocarcinoma, gestational trophoblastic tumor, giant celltumor of bone, glioblastoma multiforme, glioma, gliomatosis cerebri,glomus tumor, glucagonoma, gonadoblastoma, granulosa cell tumor, hairycell leukemia, head and neck cancer, heart cancer, hemangioblastoma,hemangiopericytoma, hemangiosarcoma, hematological malignancy,hepatocellular carcinoma, hepatosplenic T-cell lymphoma, Hodgkinlymphoma, hypopharyngeal cancer, hypothalamic glioma, inflammatorybreast cancer, intraocular melanoma, islet cell carcinoma, juvenilemyelomonocytic leukemia, Kaposi's sarcoma, kidney cancer, klatskintumor, krukenberg tumor, laryngeal cancer, lentigo maligna melanoma,leukemia, lip and oral cavity cancer, liposarcoma, lung cancer, luteoma,lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoid leukemia,lymphoma, macroglobulinemia, malignant fibrous histiocytoma, malignantglioma, malignant mesothelioma, malignant peripheral nerve sheath tumor,malignant rhabdoid tumor, malignant triton tumor, malt lymphoma, mantlecell lymphoma, mast cell leukemia, mediastinal germ cell tumor,mediastinal tumor, medullary thyroid cancer, medulloblastoma,medulloepithelioma, melanoma, meningioma, merkel cell carcinoma,mesothelioma, metastatic squamous neck cancer with occult primary,metastatic urothelial carcinoma, mixed mullerian tumor, monocyticleukemia, mouth cancer, mucinous tumor, multiple endocrine neoplasiasyndrome, multiple myeloma, mycosis fungoides, myelodysplastic disease,myeloid leukemia, myeloid sarcoma, myeloproliferative disease, myxoma,nasal cavity cancer, nasopharyngeal cancer, neoplasm, neurinoma,neuroblastoma, neurofibroma, neuroma, nodular melanoma, non-Hodgkinlymphoma, nonmelanoma skin cancer, non-small cell lung cancer, ocularoncology, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nervesheath meningioma, oral cancer, oropharyngeal cancer, osteosarcoma,ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor,ovarian low malignant potential tumor, pancoast tumor, pancreaticcancer, papillary thyroid cancer, papillomatosis, paraganglioma,paranasal sinus cancer, parathyroid cancer, penile cancer, perivascularepithelioid cell tumor, pharyngeal cancer, pheochromocytoma, pinealparenchymal tumor of intermediate differentiation, pineoblastoma,pituicytoma, pituitary adenoma, pituitary tumor, plasma cell neoplasm,pleuropulmonary blastoma, polyembryoma, precursor T-lymphoblasticlymphoma, primitive neuroectodermal tumor, prostate cancer, pseudomyxomaperitonei, rectal cancer, renal cell carcinoma, retinoblastoma,rhabdomyoma, rhabdomyosarcoma, Richter's transformation, sacrococcygealteratoma, salivary gland cancer, sarcoma, schwannomatosis, sebaceousgland carcinoma, secondary neoplasm, seminoma, serous tumor,Sertoli-Leydig cell tumor, sex cord-stromal tumor, sezary syndrome,signet ring cell carcinoma, skin cancer, small blue round cell tumor,small cell carcinoma, small cell lung cancer, small cell lymphoma, smallintestine cancer, soft tissue sarcoma, somatostatinoma, soot wart,spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma,stomach cancer, superficial spreading melanoma, supratentorial primitiveneuroectodermal tumor, surface epithelial-stromal tumor, synovialsarcoma, T-cell acute lymphoblastic leukemia, T-cell large granularlymphocyte leukemia, T-cell leukemia, T-cell lymphoma, T-cellprolymphocytic leukemia, teratoma, terminal lymphatic cancer, testicularcancer, thecoma, throat cancer, thymic carcinoma, thymoma, thyroidcancer, transitional cell cancer of renal pelvis and ureter,transitional cell carcinoma, urachal cancer, urethral cancer, urogenitalneoplasm, uterine sarcoma, uveal melanoma, vaginal cancer, vernermorrison syndrome, verrucous carcinoma, visual pathway glioma, vulvarcancer, Waldenstrom's macroglobulinemia, Warthin's tumor, Wilms' tumoror any combination thereof.

In some embodiments, the methods of administering a CD73 inhibitordescribed herein are applied to the treatment of cancers of the adrenalglands, blood, bone marrow, brain, breast, cervix, colon, head and neck,kidney, liver, lung, ovary, pancreas, plasma cells, rectum, retina,skin, spine, throat or any combination thereof.

Certain embodiments contemplate a human subject such as a subject thathas been diagnosed as having or being at risk for developing oracquiring a proliferative disorder condition. Certain other embodimentscontemplate a non-human subject, for example a non-human primate such asa macaque, chimpanzee, gorilla, vervet, orangutan, baboon or othernon-human primate, including such non-human subjects that can be knownto the art as preclinical models. Certain other embodiments contemplatea non-human subject that is a mammal, for example, a mouse, rat, rabbit,pig, sheep, horse, bovine, goat, gerbil, hamster, guinea pig or othermammal. There are also contemplated other embodiments in which thesubject or biological source can be a non-mammalian vertebrate, forexample, another higher vertebrate, or an avian, amphibian or reptilianspecies, or another subject or biological source. In certain embodimentsof the present invention, a transgenic animal is utilized. A transgenicanimal is a non-human animal in which one or more of the cells of theanimal includes a nucleic acid that is non-endogenous (i.e.,heterologous) and is present as an extrachromosomal element in a portionof its cell or stably integrated into its germ line DNA (i.e., in thegenomic sequence of most or all of its cells).

Therapeutic Efficacy: In some embodiments, therapeutic efficacy ismeasured based on an effect of treating a proliferative disorder, suchas cancer. In general, therapeutic efficacy of the methods andcompositions of the invention, with regard to the treatment of aproliferative disorder (e.g. cancer, whether benign or malignant), maybe measured by the degree to which the methods and compositions promoteinhibition of tumor cell proliferation, the inhibition of tumorvascularization, the eradication of tumor cells, the reduction in therate of growth of a tumor, and/or a reduction in the size of at leastone tumor. Several parameters to be considered in the determination oftherapeutic efficacy are discussed herein. The proper combination ofparameters for a particular situation can be established by theclinician. The progress of the inventive method in treating cancer(e.g., reducing tumor size or eradicating cancerous cells) can beascertained using any suitable method, such as those methods currentlyused in the clinic to track tumor size and cancer progress. The primaryefficacy parameter used to evaluate the treatment of cancer by theinventive method and compositions preferably is a reduction in the sizeof a tumor. Tumor size can be figured using any suitable technique, suchas measurement of dimensions, or estimation of tumor volume usingavailable computer software, such as FreeFlight software developed atWake Forest University that enables accurate estimation of tumor volume.Tumor size can be determined by tumor visualization using, for example,CT, ultrasound, SPECT, spiral CT, MRI, photographs, and the like. Inembodiments where a tumor is surgically resected after completion of thetherapeutic period, the presence of tumor tissue and tumor size can bedetermined by gross analysis of the tissue to be resected, and/or bypathological analysis of the resected tissue.

In some desirable embodiments, the growth of a tumor is stabilized(i.e., one or more tumors do not increase more than 1%, 5%, 10%, 15%, or20% in size, and/or do not metastasize) as a result of the inventivemethod and compositions. In some embodiments, a tumor is stabilized forat least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more weeks. Insome embodiments, a tumor is stabilized for at least about 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, or more months. In some embodiments, a tumoris stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or moreyears. Preferably, the inventive method reduces the size of a tumor atleast about 5% (e.g., at least about 10%, 15%, 20%, or 25%). Morepreferably, tumor size is reduced at least about 30% (e.g., at leastabout 35%, 40%, 45%, 50%, 55%, 60%, or 65%). Even more preferably, tumorsize is reduced at least about 70% (e.g., at least about 75%, 80%, 85%,90%, or 95%). Most preferably, the tumor is completely eliminated, orreduced below a level of detection. In some embodiments, a subjectremains tumor free (e.g. in remission) for at least about 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, or more weeks following treatment. In someembodiments, a subject remains tumor free for at least about 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, or more months following treatment. In someembodiments, a subject remains tumor free for at least about 1, 2, 3, 4,5, 6, 7, 8, 9, 10, or more years after treatment.

In some embodiments, the efficacy of the inventive method in reducingtumor size can be determined by measuring the percentage of necrotic(i.e., dead) tissue of a surgically resected tumor following completionof the therapeutic period. In some further embodiments, a treatment istherapeutically effective if the necrosis percentage of the resectedtissue is greater than about 20% (e.g., at least about 30%, 40%, 50%,60%, 70%, 80%, 90%, or 100%), more preferably about 90% or greater(e.g., about 90%, 95%, or 100%). Most preferably, the necrosispercentage of the resected tissue is 100%, that is, no tumor tissue ispresent or detectable.

The efficacy of the inventive method can be determined by a number ofsecondary parameters. Examples of secondary parameters include, but arenot limited to, detection of new tumors, detection of tumor antigens ormarkers (e.g., CEA, PSA, or CA-125), biopsy, surgical downstaging (i.e.,conversion of the surgical stage of a tumor from unresectable toresectable), PET scans, survival, disease progression-free survival,time to disease progression, quality of life assessments such as theClinical Benefit Response Assessment, and the like, all of which canpoint to the overall progression (or regression) of cancer in a human.Biopsy is particularly useful in detecting the eradication of cancerouscells within a tissue. Radioimmunodetection (RAID) is used to locate andstage tumors using serum levels of markers (antigens) produced by and/orassociated with tumors (“tumor markers” or “tumor-associated antigens”),and can be useful as a pre-treatment diagnostic predicate, apost-treatment diagnostic indicator of recurrence, and a post-treatmentindicator of therapeutic efficacy. Examples of tumor markers ortumor-associated antigens that can be evaluated as indicators oftherapeutic efficacy include, but are not limited to, carcinembryonicantigen (CEA), prostate-specific antigen (PSA), CA-125, CA19-9,ganglioside molecules (e.g., GM2, GD2, and GD3), MART-1, heat shockproteins (e.g., gp96), sialyl Tn (STn), tyrosinase, MUC-1, HER-2/neu,c-erb-B2, KSA, PSMA, p53, RAS, EGF-R, VEGF, MAGE, and gp100. Othertumor-associated antigens are known in the art. RAID technology incombination with endoscopic detection systems also can efficientlydistinguish small tumors from surrounding tissue (see, for example, U.S.Pat. No. 4,932,412).

In additional desirable embodiments, the treatment of cancer in a humanpatient in accordance with the inventive method is evidenced by one ormore of the following results: (a) the complete disappearance of a tumor(i.e., a complete response), (b) about a 25% to about a 50% reduction inthe size of a tumor for at least four weeks after completion of thetherapeutic period as compared to the size of the tumor beforetreatment, (c) at least about a 50% reduction in the size of a tumor forat least four weeks after completion of the therapeutic period ascompared to the size of the tumor before the therapeutic period, and (d)at least a 2% decrease (e.g., about a 5%, 10%, 20%, 30%, 40%, 50%, 60%,70%, 80% or 90% decrease) in a specific tumor-associated antigen levelat about 4-12 weeks after completion of the therapeutic period ascompared to the tumor-associated antigen level before the therapeuticperiod. While at least a 2% decrease in a tumor-associated antigen levelis preferred, any decrease in the tumor-associated antigen level isevidence of treatment of a cancer in a patient by the inventive method.For example, with respect to unresectable, locally advanced pancreaticcancer, treatment can be evidenced by at least a 10% decrease in theCA19-9 tumor-associated antigen level at 4-12 weeks after completion ofthe therapeutic period as compared to the CA19-9 level before thetherapeutic period. Similarly, with respect to locally advanced rectalcancer, treatment can be evidenced by at least a 10% decrease in the CEAtumor-associated antigen level at 4-12 weeks after completion of thetherapeutic period as compared to the CEA level before the therapeuticperiod.

With respect to quality of life assessments, such as the ClinicalBenefit Response Criteria, the therapeutic benefit of the treatment inaccordance with the invention can be evidenced in terms of painintensity, analgesic consumption, and/or the Karnofsky Performance Scalescore. The treatment of cancer in a human patient alternatively, or inaddition, is evidenced by (a) at least a 50% decrease (e.g., at least a60%, 70%, 80%, 90%, or 100% decrease) in pain intensity reported by apatient, such as for any consecutive four week period in the 12 weeksafter completion of treatment, as compared to the pain intensityreported by the patient before treatment, (b) at least a 50% decrease(e.g., at least a 60%, 70%, 80%, 90%, or 100% decrease) in analgesicconsumption reported by a patient, such as for any consecutive four weekperiod in the 12 weeks after completion of treatment as compared to theanalgesic consumption reported by the patient before treatment, and/or(c) at least a 20 point increase (e.g., at least a 30 point, 50 point,70 point, or 90 point increase) in the Karnofsky Performance Scale scorereported by a patient, such as for any consecutive four week period inthe 12 weeks after completion of the therapeutic period as compared tothe Karnofsky Performance Scale score reported by the patient before thetherapeutic period.

The treatment of a proliferative disorder (e.g. cancer, whether benignor malignant) in a human patient desirably is evidenced by one or more(in any combination) of the foregoing results, although alternative oradditional results of the referenced tests and/or other tests canevidence treatment efficacy.

In some embodiments, tumor size is reduced as a result of the inventivemethod preferably without significant adverse events in the subject.Adverse events are categorized or “graded” by the Cancer TherapyEvaluation Program (CTEP) of the National Cancer Institute (NCI), withGrade 0 representing minimal adverse side effects and Grade 4representing the most severe adverse events. Desirably, the inventivemethod is associated with minimal adverse events, e.g. Grade 0, Grade 1,or Grade 2 adverse events, as graded by the CTEP/NCI. However, asdiscussed herein, reduction of tumor size, although preferred, is notrequired in that the actual size of tumor may not shrink despite theeradication of tumor cells. Eradication of cancerous cells is sufficientto realize a therapeutic effect. Likewise, any reduction in tumor sizeis sufficient to realize a therapeutic effect.

Detection, monitoring and rating of various cancers in a human arefurther described in Cancer Facts and Figures 2001, American CancerSociety, New York, N.Y., and International Patent Application WO01/24684. Accordingly, a clinician can use standard tests to determinethe efficacy of the various embodiments of the inventive method intreating cancer. However, in addition to tumor size and spread, theclinician also may consider quality of life and survival of the patientin evaluating efficacy of treatment.

In some embodiments, administration of a CD73 inhibitor providesimproved therapeutic efficacy. Improved efficacy may be measured usingany method known in the art, including but not limited to thosedescribed herein. In some embodiments, the improved therapeutic efficacyis an improvement of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%,75%, 80%, 90%, 95%, 100%, 110%, 120%, 150%, 200%, 300%, 400%, 500%,600%, 700%, 1000% or more, using an appropriate measure (e.g. tumor sizereduction, duration of tumor size stability, duration of time free frommetastatic events, duration of disease-free survival). Improved efficacymay also be expressed as fold improvement, such as at least about2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold,20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold,100-fold, 1000-fold, 10000-fold or more, using an appropriate measure(e.g. tumor size reduction, duration of tumor size stability, durationof time free from metastatic events, duration of disease-free survival).

Pharmaceutical compositions: A composition of the present disclosure maybe formulated in any suitable pharmaceutical formulation. Apharmaceutical composition of the present disclosure typically containsan active ingredient (e.g., a compound of Formulas (I), (II-A), (II-B),(III), or a pharmaceutically acceptable salt and/or coordination complexthereof), and one or more pharmaceutically acceptable excipients,carriers, including but not limited to, inert solid diluents andfillers, diluents, sterile aqueous solution and various organicsolvents, permeation enhancers, solubilizers and adjuvants. Acomposition of the present disclosure may be formulated in any suitablepharmaceutical formulation. In some embodiments, the pharmaceuticalacceptable carriers, excipients are selected from water, alcohol,glycerol, chitosan, alginate, chondroitin, Vitamin E, mineral oil, anddimethyl sulfoxide (DMSO).

Pharmaceutical formulations may be provided in any suitable form, whichmay depend on the route of administration. In some embodiments, thepharmaceutical composition disclosed herein can be formulated in dosageform for administration to a subject. In some embodiments, thepharmaceutical composition is formulated for oral, intravenous,intraarterial, aerosol, parenteral, buccal, topical, transdermal,rectal, intramuscular, subcutaneous, intraosseous, intranasal,intrapulmonary, transmucosal, inhalation, and/or intraperitonealadministration. In some embodiments, the dosage form is formulated fororal intervention administration. For example, the pharmaceuticalcomposition can be formulated in the form of a pill, a tablet, acapsule, an inhaler, a liquid suspension, a liquid emulsion, a gel, or apowder. In some embodiments, the pharmaceutical composition can beformulated as a unit dosage in liquid, gel, semi-liquid, semi-solid, orsolid form.

The amount of each compound administered will be dependent on the mammalbeing treated, the severity of the disorder or condition, the rate ofadministration, the disposition of the compound and the discretion ofthe prescribing physician. However, an effective dosage may be in therange of about 0.001 to about 100 mg per kg body weight per day, insingle or divided doses. In some instances, dosage levels below thelower limit of the aforesaid range may be more than adequate, while inother cases still larger doses may be employed without causing anyharmful side effect, e.g., by dividing such larger doses into severalsmall doses for administration throughout the day.

In some embodiments, the disclosure provides a pharmaceuticalcomposition comprising an amount of a CD73 inhibitor formulated foradministration to a subject in need thereof. In some embodiments, thepharmaceutical composition comprises between about 0.0001-500 g,0.001-250 g, 0.01-100 g, 0.1-50 g, or 1-10 g of CD73 inhibitor. In someembodiments, the pharmaceutical composition comprises about or more thanabout 0.0001 g, 0.001 g, 0.01 g, 0.1, 0.5 g, 1 g, 2 g, 3 g, 4 g, 5 g, 6g, 7 g, 8 g, 9 g, 10 g, 15 g, 20 g, 25 g, 50 g, 100 g, 200 g, 250 g, 300g, 350 g, 400 g, 450 g, 500 g, or more of a CD73 inhibitor. In someembodiments, the pharmaceutical composition comprises between 0.001-2 gof a CD73 inhibitor in a single dose. In some embodiments, thepharmaceutical composition comprises an amount between about 50-150 g ofa CD73 inhibitor. In some embodiments, the therapeutic amount can be anamount between about 0.001-0.1 g of a CD73 inhibitor. In someembodiments, the therapeutic amount can be an amount between about0.01-30 g of a CD73 inhibitor.

In some embodiments, a therapeutically effective amount of CD73inhibitor, which can be a daily amount administered over the course of aperiod of treatment, can sufficiently provide any one or more of thetherapeutic effects described herein. As an example, the therapeuticeffective amount can be in the range of about 0.001-1000 mg/kg bodyweight, 0.01-500 mg/kg body weight, 0.01-100 mg/kg body weight, 0.01-30mg/kg body weight, 0.1-200 mg/kg body weight, 3-200 mg/kg body weight,5-500 mg/kg body weight, 10-100 mg/kg body weight, 10-1000 mg/kg bodyweight, 50-200 mg/kg body weight, 100-1000 mg/kg body weight, 200-500mg/kg body weight, 250-350 mg/kg body weight, or 300-600 mg/kg bodyweight of a CD73 inhibitor. In some embodiments, the therapeutic amountcan be about or more than about 0.001 mg/kg body weight, 0.01 mg/kg bodyweight, 0.1 mg/kg body weight, 0.5 mg/kg body weight, 1 mg/kg bodyweight, 2 mg/kg body weight, 3 mg/kg body weight, 4 mg/kg body weight, 5mg/kg body weight, 6 mg/kg body weight, 7 mg/kg body weight, 8 mg/kgbody weight, 9 mg/kg body weight, 10 mg/kg body weight, 15 mg/kg bodyweight, 20 mg/kg body weight, 25 mg/kg body weight, 50 mg/kg bodyweight, 100 mg/kg body weight, 200 mg/kg body weight, 250 mg/kg bodyweight, 300 mg/kg body weight, 350 mg/kg body weight, 400 mg/kg bodyweight, 450 mg/kg body weight, 500 mg/kg body weight, 600 mg/kg bodyweight, 800 mg/kg body weight, 1000 mg/kg body weight, or more of a CD73inhibitor. In some embodiments, the effective amount is at least about0.01 mg/kg body weight of a CD73 inhibitor. In some embodiments, theeffective amount is an amount between about 0.01-30 mg/kg body weight ofa CD73 inhibitor. In some embodiments, the therapeutic amount can be anamount between about 50-150 mg/kg body weight of a CD73 inhibitor.

In some embodiments, the composition is provided in one or more unitdoses. For example, the composition can be administered in 1, 2, 3, 4,5, 6, 7, 14, 30, 60, or more doses. Such amount can be administered eachday, for example in individual doses administered once, twice, or threeor more times a day. However, dosages stated herein on a per day basisshould not be construed to require administration of the daily dose eachand every day. For example, if one of the agents is provided in asuitably slow-release form, two or more daily dosage amounts can beadministered at a lower frequency, e.g., as a depot every second day toonce a month or even longer. Most typically and conveniently for thesubject, a CD73 inhibitor can be administered once a day, for example inthe morning, in the evening or during the day.

The unit doses can be administered simultaneously or sequentially. Thecomposition can be administered for an extended treatment period.Illustratively, the treatment period can be at least about one month,for example at least about 3 months, at least about 6 months or at leastabout 1 year. In some cases, administration can continue forsubstantially the remainder of the life of the subject.

In some embodiments, the CD73 inhibitor can be administered as part of atherapeutic regimen that comprises administering one or more secondagents (e.g. 1, 2, 3, 4, 5, or more second agents), eithersimultaneously or sequentially with the CD73 inhibitor. Whenadministered sequentially, the CD73 inhibitor may be administered beforeor after the one or more second agents. When administeredsimultaneously, the CD73 inhibitor and the one or more second agents maybe administered by the same route (e.g. injections to the same location;tablets taken orally at the same time), by a different route (e.g. atablet taken orally while receiving an intravenous infusion), or as partof the same combination (e.g. a solution comprising a CD73 inhibitor andone or more second agents).

A combination treatment according to the invention may be effective overa wide dosage range. For example, in the treatment of adult humans,dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg perday, and from 5 to 40 mg per day are examples of dosages that may beused. The exact dosage will depend upon the agent selected, the route ofadministration, the form in which the compound is administered, thesubject to be treated, the body weight of the subject to be treated, andthe preference and experience of the attending physician.

Pharmaceutical composition for oral administration: In some embodiments,the disclosure provides a pharmaceutical composition for oraladministration containing at least one compound of the presentdisclosure and a pharmaceutical excipient suitable for oraladministration. The composition may be in the form of a solid, liquid,gel, semi-liquid, or semi-solid. In some embodiments, the compositionfurther comprises a second agent.

In some embodiments, the invention provides a solid pharmaceuticalcomposition for oral administration containing: (i) a CD73 inhibitor;and (ii) a pharmaceutical excipient suitable for oral administration. Insome embodiments, the composition further contains: (iii) a third agentor even a fourth agent. In some embodiments, each compound or agent ispresent in a therapeutically effective amount. In other embodiments, oneor more compounds or agents is present in a sub-therapeutic amount, andthe compounds or agents act synergistically to provide a therapeuticallyeffective pharmaceutical composition.

Pharmaceutical compositions of the disclosure suitable for oraladministration can be presented as discrete dosage forms, such as hardor soft capsules, cachets, troches, lozenges, or tablets, or liquids oraerosol sprays each containing a predetermined amount of an activeingredient as a powder or in granules, a solution, or a suspension in anaqueous or non-aqueous liquid, an oil-in-water emulsion, or awater-in-oil liquid emulsion, or dispersible powders or granules, orsyrups or elixirs. Such dosage forms can be prepared by any of themethods of pharmacy, which typically include the step of bringing theactive ingredient(s) into association with the carrier. In general, thecomposition are prepared by uniformly and intimately admixing the activeingredient(s) with liquid carriers or finely divided solid carriers orboth, and then, if necessary, shaping the product into the desiredpresentation. For example, a tablet can be prepared by compression ormolding, optionally with one or more accessory ingredients. Compressedtablets can be prepared by compressing in a suitable machine the activeingredient(s) in a free-flowing form such as powder or granules,optionally mixed with an excipient such as, but not limited to, abinder, a lubricant, an inert diluent, and/or a surface active ordispersing agent. Molded tablets can be made by molding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent.

This disclosure further encompasses anhydrous pharmaceutical compositionand dosage forms comprising an active ingredient, since water canfacilitate the degradation of some compounds. For example, water may beadded (e.g., 5%) in the pharmaceutical arts as a means of simulatinglong-term storage in order to determine characteristics such asshelf-life or the stability of formulations over time. Anhydrouspharmaceutical compositions and dosage forms of the disclosure can beprepared using anhydrous or low moisture containing ingredients and lowmoisture or low humidity conditions. Pharmaceutical compositions anddosage forms of the disclosure which contain lactose can be madeanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected. An anhydrouspharmaceutical composition may be prepared and stored such that itsanhydrous nature is maintained. Accordingly, anhydrous compositions maybe packaged using materials known to prevent exposure to water such thatthey can be included in suitable formulary kits. Examples of suitablepackaging include, but are not limited to, hermetically sealed foils,plastic or the like, unit dose containers, blister packs, and strippacks.

An active ingredient can be combined in an intimate admixture with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier can take a wide variety of formsdepending on the form of preparation desired for administration. Inpreparing the composition for an oral dosage form, any of the usualpharmaceutical media can be employed as carriers, such as, for example,water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents, and the like in the case of oral liquid preparations(such as suspensions, solutions, and elixirs) or aerosols; or carrierssuch as starches, sugars, micro-crystalline cellulose, diluents,granulating agents, lubricants, binders, and disintegrating agents canbe used in the case of oral solid preparations, in some embodimentswithout employing the use of lactose. For example, suitable carriersinclude powders, capsules, and tablets, with the solid oralpreparations. If desired, tablets can be coated by standard aqueous ornonaqueous techniques.

Binders suitable for use in pharmaceutical composition and dosage formsinclude, but are not limited to, corn starch, potato starch, or otherstarches, gelatin, natural and synthetic gums such as acacia, sodiumalginate, alginic acid, other alginates, powdered tragacanth, guar gum,cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixturesthereof.

Examples of suitable fillers for use in the pharmaceutical compositionand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

Disintegrants may be used in the composition of the disclosure toprovide tablets that disintegrate when exposed to an aqueousenvironment. Too much of a disintegrant may produce tablets which maydisintegrate in the bottle. Too little may be insufficient fordisintegration to occur and may alter the rate and extent of release ofthe active ingredient(s) from the dosage form. A sufficient amount ofdisintegrant that is neither too little nor too much to detrimentallyalter the release of the active ingredient(s) may be used to form thedosage forms of the compounds disclosed herein. The amount ofdisintegrant used may vary based upon the type of formulation and modeof administration, and may be readily discernible to those of ordinaryskill in the art. About 0.5 to about 15 weight percent of disintegrant,or about 1 to about 5 weight percent of disintegrant, may be used in thepharmaceutical composition. Disintegrants that can be used to formpharmaceutical composition and dosage forms of the disclosure include,but are not limited to, agar-agar, alginic acid, calcium carbonate,microcrystalline cellulose, croscarmellose sodium, crospovidone,polacrilin potassium, sodium starch glycolate, potato or tapioca starch,other starches, pre-gelatinized starch, other starches, clays, otheralgins, other celluloses, gums or mixtures thereof.

Lubricants which can be used to form pharmaceutical composition anddosage forms of the disclosure include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, ormixtures thereof. Additional lubricants include, for example, a syloidsilica gel, a coagulated aerosol of synthetic silica, or mixturesthereof. A lubricant can optionally be added, in an amount of less thanabout 1 weight percent of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are desired for oraladministration, the active ingredient therein may be combined withvarious sweetening or flavoring agents, coloring matter or dyes and, ifso desired, emulsifying and/or suspending agents, together with suchdiluents as water, ethanol, propylene glycol, glycerin and variouscombinations thereof.

The tablets can be uncoated or coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed. Formulations for oral use can also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example, peanut oil, liquidparaffin or olive oil.

Surfactant which can be used to form pharmaceutical composition anddosage forms of the disclosure include, but are not limited to,hydrophilic surfactants, lipophilic surfactants, and mixtures thereof.That is, a mixture of hydrophilic surfactants may be employed, a mixtureof lipophilic surfactants may be employed, or a mixture of at least onehydrophilic surfactant and at least one lipophilic surfactant may beemployed.

A suitable hydrophilic surfactant may generally have an HLB value of atleast 10, while suitable lipophilic surfactants may generally have anHLB value of or less than about 10. An empirical parameter used tocharacterize the relative hydrophilicity and hydrophobicity of non-ionicamphiphilic compounds is the hydrophilic-lipophilic balance (“HLB”value). Surfactants with lower HLB values are more lipophilic orhydrophobic, and have greater solubility in oils, while surfactants withhigher HLB values are more hydrophilic, and have greater solubility inaqueous solutions. Hydrophilic surfactants are generally considered tobe those compounds having an HLB value greater than about 10, as well asanionic, cationic, or zwitterionic compounds for which the HLB scale isnot generally applicable. Similarly, lipophilic (i.e., hydrophobic)surfactants are compounds having an HLB value equal to or less thanabout 10. However, HLB value of a surfactant is merely a rough guidegenerally used to enable formulation of industrial, pharmaceutical andcosmetic emulsions.

Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionicsurfactants include, but are not limited to, alkylammonium salts;fusidic acid salts; fatty acid derivatives of amino acids,oligopeptides, and polypeptides; glyceride derivatives of amino acids,oligopeptides, and polypeptides; lecithins and hydrogenated lecithins;lysolecithins and hydrogenated lysolecithins; phospholipids andderivatives thereof; lysophospholipids and derivatives thereof;carnitine fatty acid ester salts; salts of alkylsulfates; fatty acidsalts; sodium docusate; acylactylates; mono- and di-acetylated tartaricacid esters of mono- and di-glycerides; succinylated mono- anddi-glycerides; citric acid esters of mono- and di-glycerides; andmixtures thereof.

Within the aforementioned group, ionic surfactants include, by way ofexample: lecithins, lysolecithin, phospholipids, lysophospholipids andderivatives thereof; carnitine fatty acid ester salts; salts ofalkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono-and di-acetylated tartaric acid esters of mono- and di-glycerides;succinylated mono- and di-glycerides; citric acid esters of mono- anddi-glycerides; and mixtures thereof.

Ionic surfactants may be the ionized forms of lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,phosphatidic acid, phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholylsarcosine, caproate, caprylate,caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate,linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate,lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, andsalts and mixtures thereof.

Hydrophilic non-ionic surfactants may include, but not limited to,alkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; polyoxyalkylene alkyl ethers such as polyethyleneglycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethyleneglycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esterssuch as polyethylene glycol fatty acids monoesters and polyethyleneglycol fatty acids diesters; polyethylene glycol glycerol fatty acidesters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fattyacid esters such as polyethylene glycol sorbitan fatty acid esters;hydrophilic transesterification products of a polyol with at least onemember of the group of glycerides, vegetable oils, hydrogenatedvegetable oils, fatty acids, and sterols; polyoxyethylene sterols,derivatives, and analogues thereof; polyoxyethylated vitamins andderivatives thereof; polyoxyethylene-polyoxypropylene block copolymers;and mixtures thereof; polyethylene glycol sorbitan fatty acid esters andhydrophilic transesterification products of a polyol with at least onemember of the group of triglycerides, vegetable oils, and hydrogenatedvegetable oils. The polyol may be glycerol, ethylene glycol,polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or asaccharide.

Other hydrophilic-non-ionic surfactants include, without limitation,PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate,PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate,PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryllaurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenatedcastor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitanlaurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearylether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate,sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octylphenol series, and poloxamers.

Suitable lipophilic surfactants include, by way of example only: fattyalcohols; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lower alcohol fatty acids esters; propylene glycol fatty acidesters; sorbitan fatty acid esters; polyethylene glycol sorbitan fattyacid esters; sterols and sterol derivatives; polyoxyethylated sterolsand sterol derivatives; polyethylene glycol alkyl ethers; sugar esters;sugar ethers; lactic acid derivatives of mono- and di-glycerides;hydrophobic transesterification products of a polyol with at least onemember of the group of glycerides, vegetable oils, hydrogenatedvegetable oils, fatty acids and sterols; oil-soluble vitamins/vitaminderivatives; and mixtures thereof. Within this group, preferredlipophilic surfactants include glycerol fatty acid esters, propyleneglycol fatty acid esters, and mixtures thereof, or are hydrophobictransesterification products of a polyol with at least one member of thegroup of vegetable oils, hydrogenated vegetable oils, and triglycerides.

In one embodiment, the composition may include a solubilizer to ensuregood solubilization and/or dissolution of the compound of the presentdisclosure and to minimize precipitation of the compound of the presentdisclosure. This can be especially important for composition fornon-oral use, e.g., composition for injection. A solubilizer may also beadded to increase the solubility of the hydrophilic drug and/or othercomponents, such as surfactants, or to maintain the composition as astable or homogeneous solution or dispersion.

Examples of suitable solubilizers include, but are not limited to, thefollowing: alcohols and polyols, such as ethanol, isopropanol, butanol,benzyl alcohol, ethylene glycol, propylene glycol, butanediols andisomers thereof, glycerol, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, polyethylene glycol, polypropyleneglycol, polyvinylalcohol, hydroxypropyl methylcellulose and othercellulose derivatives, cyclodextrins and cyclodextrin derivatives;ethers of polyethylene glycols having an average molecular weight ofabout 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether(glycofurol) or methoxy PEG; amides and other nitrogen-containingcompounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam,N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esterssuch as ethyl propionate, tributylcitrate, acetyl triethylcitrate,acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate,ethyl butyrate, triacetin, propylene glycol monoacetate, propyleneglycol diacetate, ε-caprolactone and isomers thereof, 6-valerolactoneand isomers thereof, β-butyrolactone and isomers thereof; and othersolubilizers known in the art, such as dimethyl acetamide, dimethylisosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycolmonoethyl ether, and water.

Mixtures of solubilizers may also be used. Examples include, but notlimited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate,dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol,transcutol, propylene glycol, and dimethyl isosorbide. Particularlypreferred solubilizers include sorbitol, glycerol, triacetin, ethylalcohol, PEG-400, glycofurol and propylene glycol.

The amount of solubilizer that can be included is not particularlylimited. The amount of a given solubilizer may be limited to abioacceptable amount, which may be readily determined by one of skill inthe art. In some circumstances, it may be advantageous to includeamounts of solubilizers far in excess of bioacceptable amounts, forexample to maximize the concentration of the drug, with excesssolubilizer removed prior to providing the composition to a patientusing conventional techniques, such as distillation or evaporation. Ifpresent, the solubilizer can be in a weight ratio of 10%, 25%, 50%,100%, or up to about 200% by weight, based on the combined weight of thedrug, and other excipients. If desired, very small amounts ofsolubilizer may also be used, such as 5%, 2%, 1% or even less.Typically, the solubilizer may be present in an amount of about 1% toabout 100%, more typically about 5% to about 25% by weight.

The composition can further include one or more pharmaceuticallyacceptable additives and excipients. Such additives and excipientsinclude, without limitation, detackifiers, anti-foaming agents,buffering agents, polymers, antioxidants, preservatives, chelatingagents, viscomodulators, tonicifiers, flavorants, colorants, odorants,opacifiers, suspending agents, binders, fillers, plasticizers,lubricants, and mixtures thereof.

In addition, an acid or a base may be incorporated into the compositionto facilitate processing, to enhance stability, or for other reasons.Examples of pharmaceutically acceptable bases include amino acids, aminoacid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide,sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate,magnesium hydroxide, magnesium aluminum silicate, synthetic aluminumsilicate, synthetic hydrocalcite, magnesium aluminum hydroxide,diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine,triethylamine, triisopropanolamine, trimethylamine,tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable arebases that are salts of a pharmaceutically acceptable acid, such asacetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonicacid, amino acids, ascorbic acid, benzoic acid, boric acid, butyricacid, carbonic acid, citric acid, fatty acids, formic acid, fumaricacid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lacticacid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionicacid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinicacid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonicacid, uric acid, and the like. Salts of polyprotic acids, such as sodiumphosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphatecan also be used. When the base is a salt, the cation can be anyconvenient and pharmaceutically acceptable cation, such as ammonium,alkali metals, alkaline earth metals, and the like. Example may include,but not limited to, sodium, potassium, lithium, magnesium, calcium andammonium.

Suitable acids are pharmaceutically acceptable organic or inorganicacids. Examples of suitable inorganic acids include hydrochloric acid,hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boricacid, phosphoric acid, and the like. Examples of suitable organic acidsinclude acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid, uric acid and the like.

Pharmaceutical composition for injection: In some embodiments, thedisclosure provides a pharmaceutical composition for injectioncontaining a compound of the present disclosure and a pharmaceuticalexcipient suitable for injection. Components and amounts of agents inthe composition are as described herein.

The forms in which the novel composition of the present disclosure maybe incorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and thelike (and suitable mixtures thereof), cyclodextrin derivatives, andvegetable oils may also be employed. The proper fluidity can bemaintained, for example, by the use of a coating, such as lecithin, forthe maintenance of the required particle size in the case of dispersionand by the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating the compoundof the present disclosure in the required amount in the appropriatesolvent with various other ingredients as enumerated above, as required,followed by filtered sterilization. Generally, dispersions are preparedby incorporating the various sterilized active ingredients into asterile vehicle which contains the basic dispersion medium and therequired other ingredients from those enumerated above. In the case ofsterile powders for the preparation of sterile injectable solutions,certain desirable methods of preparation are vacuum-drying andfreeze-drying techniques which yield a powder of the active ingredientplus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Other pharmaceutical compositions: Pharmaceutical compositions may alsobe prepared from composition described herein and one or morepharmaceutically acceptable excipients suitable for transdermal,inhalative, sublingual, buccal, rectal, intraosseous, intraocular,intranasal, epidural, or intraspinal administration. Preparations forsuch pharmaceutical composition are well-known in the art. See, e.g.,See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G,eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002;Pratt and Taylor, eds., Principles of Drug Action, Third Edition,Churchill Livingston, N.Y., 1990; Katzung, ed., Basic and ClinicalPharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman,eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGrawHill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., LippincottWilliams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia,Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all ofwhich are incorporated by reference herein in their entirety.

The compounds of the present invention can also be administered in theform of liposomes. As is known in the art, liposomes are generallyderived from phospholipids or other lipid substances. Liposomes areformed by mono- or multilamellar hydrated liquid crystals that aredispersed in an aqueous medium. Any non-toxic, physiologicallyacceptable and metabolizable lipid capable of forming liposomes can beused. The present compositions in liposome form can contain, in additionto a compound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andphosphatidyl cholines (lecithins), both natural and synthetic. Methodsto form liposomes are known in the art. See, for example, Prescott, Ed.,“Methods in Cell Biology”, Volume XIV, ISBN: 978-0-12-564114-2, AcademicPress, New York, N.W., p. 33 (1976) and Medina, Zhu, and Kairemo,“Targeted liposomal drug delivery in cancer”, Current Pharm. Des. 10:2981-2989, 2004. For additional information regarding drug formulationand administration, see “Remington: The Science and Practice ofPharmacy,” Lippincott Williams & Wilkins, Philadelphia, ISBN-10:0781746736, 21^(st) Edition (2005).

The invention also provides kits. The kits may include a CD73 inhibitorand one or more additional agents in suitable packaging with writtenmaterial that can include instructions for use, discussion of clinicalstudies, listing of side effects, and the like. Such kits may alsoinclude information, such as scientific literature references, packageinsert materials, clinical trial results, and/or summaries of these andthe like, which indicate or establish the activities and/or advantagesof the composition, and/or which describe dosing, administration, sideeffects, drug interactions, or other information useful to the healthcare provider. Such information may be based on the results of variousstudies, for example, studies using experimental animals involving invivo models and studies based on human clinical trials. The kit mayfurther contain another agent. In some embodiments, the compound of thepresent invention and the agent are provided as separate compositions inseparate containers within the kit. In some embodiments, the compound ofthe present invention and the agent are provided as a single compositionwithin a container in the kit. Suitable packaging and additionalarticles for use (e.g., measuring cup for liquid preparations, foilwrapping to minimize exposure to air, and the like) are known in the artand may be included in the kit. Kits described herein can be provided,marketed and/or promoted to health providers, including physicians,nurses, pharmacists, formulary officials, and the like. Kits may also,in some embodiments, be marketed directly to the consumer.

Combination therapies: The present invention also provides methods forfurther combination therapies in which, in addition to a CD73 inhibitor,one or more second agents known to modulate other pathways, or othercomponents of the same pathway, or even overlapping sets of targetproteins is used, or a pharmaceutically acceptable salt, ester, prodrug,solvate, hydrate or derivative thereof. In one aspect, such therapyincludes but is not limited to the combination of the compositioncomprising a CD73 inhibitor as described herein with one or more ofother CD73 inhibitors as described herein, chemotherapeutic agents,therapeutic antibodies, and radiation treatment, to provide, wheredesired, a synergistic or additive therapeutic effect.

Second agents useful in the methods of the invention include any agentcapable of modulating a target molecule, either directly or indirectly.Non-limiting examples of target molecules modulated by second agentsinclude enzymes, enzyme substrates, products of transitions, antibodies,antigens, membrane proteins, nuclear proteins, cytosolic proteins,mitochondrial proteins, lysosomal proteins, scaffold proteins, lipidrafts, phosphoproteins, glycoproteins, membrane receptors,G-protein-coupled receptors, nuclear receptors, protein tyrosinekinases, protein serine/threonine kinases, phosphatases, proteases,hydrolases, lipases, phospholipases, ligases, reductases, oxidases,synthases, transcription factors, ion channels, RNA, DNA, RNAse, DNAse,phospholipids, sphingolipids, nuclear receptors, ion channel proteins,nucleotide-binding proteins, calcium-binding proteins, chaperones, DNAbinding proteins, RNA binding proteins, scaffold proteins, tumorsuppressors, cell cycle proteins, and histones.

Second agents may target one or more signaling molecules including butnot limited to the following: 4EPB-1, 5-lipoxygenase, A1, Ab1,Acetyl-CoAa Carboxylase, actin, adaptor/scaffold proteins, adenylylcyclase receptors, adhesion molecules, AFT, Akt1, Akt2, Akt3, ALK,AMPKs, APC/C, ARaf, Arf-GAPs, Arfs, ASK, ASK1, asparagine hydroxylaseFIH transferases, ATF2, ATF-2, ATM, ATP citrate lyase, ATR, Auroras, Bcell adaptor for PI3-kinase (BCAP), Bad, Bak, Bax, Bcl-2, Bcl-B, Bcl-w,Bcl-XL, Bid, Bik, Bim, BLNK, Bmf, BMP receptors, Bok, BRAF, Btk, Bub,cadherins, CaMKs, Casein kinases, Caspase 2, Caspase 3, Caspase 6,Caspase 7, Caspase 8, Caspase 9, caspases, catenins, cathepsins,caveolins, Cb1, CBP/P300 family, CD45, CDC25 phosphatases, Cdc42, Cdk 1,Cdk 2, Cdk 4, Cdk 6, Cdk 7, Cdks, CENPs, Chk1, Chk2, CLKs, Cot, cRaf,CREB, Crk, CrkL, Csk, Cyclin A, Cyclin B, Cyclin D, Cyclin E, Db1,deacetylases, DLK, DNA methyl transferases, DNA-PK, Dok, DualSpecificity phosphatases (DUSPs), E2Fs, eg5/KSP, Egr-1, eIF4E-bindingprotein, Elk, elongation factors, endosomal sorting complex required fortransport (ESCRT) proteins, Eph receptors, Erks, esterases, Ets, Eyesabsent (EYA) tyrosine phosphatases, FAK, Fas associated death domain(FADD), FGF receptors, Fgr, focal adhesion kinase, fodrin, Fos, FOXO,Fyn, GAD, Grb2, Grb2 associated binder (GAB), GSK3a, GSK30, H-Ras,H3K27, Hdm, HER receptors, HIFs, histone acetylases, histonedeacetylases, Histone H3K4 demethylases, HMGA, Hrk, Hsp27, Hsp70,Hsp90s, hydrolases, hydroxylases, IAPs, IGF receptors, IKKs, IL-2, IL-4,IL-6, IL-8, ILK, Immunoglobulin-like adhesion molecules, initiationfactors, inositol phosphatases, Insulin receptor, integrins, interferonα, interferon β, IRAKs, Jak1, Jak2, Jak3, JHDM2A, Jnks, K-Ras, Kitreceptor, KSR, LAR phosphatase, LAT, Lck, Lim kinase, LKB-1, Lowmolecular weight tyrosine phosphatase, Lyn, MAP kinase phosphatases(MKPs), MAPKAPKs, MARKs, Mcl-1, Mek 1, Mek 2, MEKKs, MELK, Met receptor,metabolic enzymes, metalloproteinases, MKK3/6, MKK4/7, MLKs, MNKs,molecular chaperones, Mos, mTOR, multi-drug resistance proteins,muscarinic receptors, Myc, MyD88, myosin, myosin binding proteins,myotubularins, MYST family, Myt 1, N-Ras, Nck, NFAT, NIK, nitric oxidesynthase, Non receptor tyrosine phosphatases (NPRTPs), Noxa, nucleosidetransporters, p130CAS, p14Arf, p16, p21CIP, p27KIP, p38s, p53, p70S6Kinase, p90Rsks, PAKs, paxillin, PDGF receptors, PDK1, P-Glycoprotein,phopsholipases, phosphoinositide kinases, PI3-Kinase class 1, Pim1,Pim2, Pim3, Pin1 prolyl isomerase, PKAs, PKCs, PKR, potassium channels,PP1, PP2A, PP2B, PP2C, PP5, PRK, Prks, prolyl-hydroxylases PHD-1,prostaglandin synthases, pS6, PTEN, Puma, RABs, Rac, Ran, Ras-GAP,R^(b), Receptor protein tyrosine phosphatases (RPTPs), Rel-A (p65-NFKB),Ret, RHEB, Rho, Rho-GAPs, RIP, RNA polymerase, ROCK 1, ROCK 2,SAPK/JNK1,2,3, SCF ubiquitination ligase complex, selectins, separase,serine phosphatases, SGK1, SGK2, SGK3, Shc, SHIPs, SHPs, sirtuins, SLAP,Slingshot phosphatases (SSH), Smac, SMADs, small molecular weightGTPases, sodium channels, Sos, Spl, sphingomyelinases, sphingosinekinases, Src, SRFs, STAT1, STAT3, STAT4, STAT5, STAT6, suppressors ofcytokine signaling (SOCs), Syk, T-bet, T-Cell leukemia family, TCFs,TGFβ receptors, Tiam, TIE1, TIE2, topoisomerases, Tp1, TRADD, TRAF2, Trkreceptors, TSC1,2, tubulin, Tyk2, ubiquitin proteases, urokinase-typeplasminogen activator (uPA) and uPA receptor (uPAR) system, UTX, Vav,VEGF receptors, vesicular protein sorting (Vsps), VHL, Wee1, WT-1, WT-1,XIAP, Yes, ZAP70, β-adrenergic receptors and β-catenin.

In one aspect, this invention also relates to methods and pharmaceuticalcompositions for inhibiting abnormal cell growth in a mammal whichcomprises an amount of a CD73 inhibitor, or a pharmaceuticallyacceptable salt, ester, prodrug, solvate, hydrate or derivative thereof,in combination with an amount of an anti-cancer agent (e.g., achemotherapeutic agent). Many chemotherapeutics are presently known inthe art and can be used in combination with the compounds of theinvention.

In some embodiments, the chemotherapeutic is selected from mitoticinhibitors, alkylating agents, anti-metabolites, intercalatingantibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes,topoisomerase inhibitors, biological response modifiers, anti-hormones,angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents,and anti-androgens. Non-limiting examples are chemotherapeutic agents,cytotoxic agents, and non-peptide small molecules such as Tykerb/Tyverb(lapatinib), Gleevec (Imatinib Mesylate), Velcade (bortezomib), Casodex(bicalutamide), Iressa (gefitinib), and Adriamycin as well as a host ofchemotherapeutic agents. Non-limiting examples of chemotherapeuticagents include 2,2′,2″-trichlorotriethylamine; 2-ethylhydrazide;aceglatone; aldophosphamide glycoside; alkyl sulfonates such asbusulfan, improsulfan and piposulfan; alkylating agents such as thiotepaand cyclosphosphamide (CYTOXAN™); aminolevulinic acid; amsacrine;anti-adrenals such as aminoglutethimide, mitotane, trilostane;antibiotics such as anthracyclins, actinomycins and bleomycins includingaclacinomysins, actinomycin, anthramycin, azaserine, bleomycins,cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin,Casodex™, chromomycins, dactinomycin, daunorubicin, detorubicin,6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin,olivomycins, peplomycin, potfiromycin, puromycin, quelamycin,rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex,zinostatin, zorubicin; anti-metabolites such as methotrexate and5-fluorouracil (5-FU); arabinoside (“Ara-C”); aziridines such asbenzodopa, carboquone, meturedopa, and uredopa; bestrabucil; bisantrene;capecitabine; cyclophosphamide; dacarbazine; defofamine; demecolcine;diaziquone; edatraxate; elfomithine; elliptinium acetate; esperamicins;ethylenimines and methylamelamines including altretamine,triethylenemelamine, trietylenephosphoramide,triethylenethiophosphaoramide and trimethylolomelamine; etoglucid; folicacid analogues such as denopterin, methotrexate, pteropterin,trimetrexate; folic acid replenisher such as frolinic acid; gacytosine;gallium nitrate; gemcitabine; hydroxyurea; lentinan; lonidamine;mannomustine; mitobronitol; mitoguazone; mitolactol; mitoxantrone;mopidamol; nitracrine; nitrogen mustards such as chlorambucil,chlornaphazine, cholophosphamide, estramustine, ifosfamide,mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard;nitrosoureas; nitrosoureas such as carmustine, chlorozotocin,fotemustine, lomustine, nimustine, ranimustine; oxazaphosphorines;pentostatin; phenamet; pipobroman; pirarubicin; podophyllinic acid;procarbazine; PSK®; purine analogs such as fludarabine,6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such asancitabine, azacitidine, 6-azauridine, carmofur, cytarabine,dideoxyuridine, doxifluridine, enocitabine, floxuridine, androgens suchas calusterone, dromostanolone propionate, epitiostanol, mepitiostane,testolactone; razoxane; retinoic acid; sizofiran; spirogermanium;taxanes, e.g., paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology,Princeton, N.J.) and docetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony,France); tenuazonic acid; thiotepa; triazenes; triaziquone; urethan;vindesine; and pharmaceutically acceptable salts, acids or derivativesof any of the above. Also included as suitable chemotherapeutic cellconditioners are anti-hormonal agents that act to regulate or inhibithormone action on tumors such as anti-estrogens including for exampletamoxifen (Nolvadex™), raloxifene, aromatase inhibiting 4(5)-imidazoles,4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, andtoremifene (Fareston); and anti-androgens such as flutamide, nilutamide,bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine;6-thioguanine; mercaptopurine; methotrexate; platinum or platinumanalogs and complexes such as cisplatin and carboplatin;anti-microtubule such as diterpenoids, including paclitaxel anddocetaxel, or Vinca alkaloids including vinblastine, vincristine,vinflunine, vindesine, and vinorelbine; etoposide (VP-16); ifosfamide;mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine;novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate;topoisomerase I and II inhibitors including camptothecins (e.g.,camptothecin-11), topotecan, irinotecan, and epipodophyllotoxins;topoisomerase inhibitor RFS 2000; epothilone A or B;difluoromethylornithine (DMFO); histone deacetylase inhibitors;compounds which induce cell differentiation processes; gonadorelinagonists; methionine aminopeptidase inhibitors; compoundstargeting/decreasing a protein or lipid kinase activity; compounds whichtarget, decrease or inhibit the activity of a protein or lipidphosphatase; anti-androgens; bisphosphonates; biological responsemodifiers; antiproliferative antibodies; heparanase inhibitors;inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasomeinhibitors; compounds used in the treatment of hematologic malignancies;compounds which target, decrease or inhibit the activity of Flt-3; Hsp90inhibitors; temozolomide (TEMODAL®); Hsp90 inhibitors such as 17-AAG(17-allylaminogeldanamycin, NSC330507), 17-DMAG(17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545),IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics;temozolomide (TEMODAL®); kinesin spindle protein inhibitors, such asSB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazinefrom CombinatoRx; MEK inhibitors such as ARRY142886 from ArrayPioPharma, AZD6244 from AstraZeneca, PD181461 or PD0325901 from Pfizer,leucovorin, EDG binders, antileukemia compounds, ribonucleotidereductase inhibitors, S-adenosylmethionine decarboxylase inhibitors,antiproliferative antibodies or other chemotherapeutic compounds. Wheredesired, the compounds or pharmaceutical composition of the presentinvention can be used in combination with commonly prescribedanti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®,Taxol®, Arimidex®, Taxotere®, and Velcade®.

This invention further relates to a method for using the compounds orpharmaceutical composition in combination with other tumor treatmentapproaches, including surgery, ionizing radiation, photodynamic therapy,or implants, e.g., with corticosteroids, hormones, or used asradiosensitizers.

One such approach may be, for example, radiation therapy in inhibitingabnormal cell growth or treating the proliferative disorder in themammal. Techniques for administering radiation therapy are known in theart, and these techniques can be used in the combination therapydescribed herein. The administration of the compound of the invention inthis combination therapy can be determined as described herein.

Radiation therapy can be administered through one of several methods, ora combination of methods, including without limitation external-beamtherapy, internal radiation therapy, implant radiation, stereotacticradiosurgery, systemic radiation therapy, radiotherapy and permanent ortemporary interstitial brachytherapy. The term “brachytherapy,” as usedherein, refers to radiation therapy delivered by a spatially confinedradioactive material inserted into the body at or near a tumor or otherproliferative tissue disease site. The term is intended withoutlimitation to include exposure to radioactive isotopes (e.g., At-211,I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, andradioactive isotopes of Lu). Suitable radiation sources for use as acell conditioner of the present invention include both solids andliquids. By way of non-limiting example, the radiation source can be aradionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source,I-125 as a solid source, or other radionuclides that emit photons, betaparticles, gamma radiation, or other therapeutic rays. The radioactivematerial can also be a fluid made from any solution of radionuclide(s),e.g., a solution of I-125 or I-131, or a radioactive fluid can beproduced using a slurry of a suitable fluid containing small particlesof solid radionuclides, such as Au-198, Y-90. Moreover, theradionuclide(s) can be embodied in a gel or radioactive micro spheres.

Without being limited by any theory, the compounds of the presentinvention can render abnormal cells more sensitive to treatment withradiation for purposes of killing and/or inhibiting the growth of suchcells. Accordingly, this invention further relates to a method forsensitizing abnormal cells in a mammal to treatment with radiation,which comprises administering to the mammal an amount of a CD73inhibitor or a pharmaceutically acceptable salt, ester, prodrug,solvate, hydrate or derivative thereof, which is effective insensitizing abnormal cells to treatment with radiation. The amount ofthe compound in this method can be determined according to the means forascertaining effective amounts of such compounds described herein.

Further therapeutic agents that can be combined with a subject compoundmay be found in Goodman and Gilman's “The Pharmacological Basis ofTherapeutics” Tenth Edition edited by Hardman, Limbird and Gilman or thePhysician's Desk Reference, both of which are incorporated herein byreference in their entirety.

In some embodiments, the compositions and methods further compriseadministering, separately or simultaneously one or more additionalagents (e.g. 1, 2, 3, 4, 5, or more). Additional agents can includethose useful in wound healing. Non-limiting examples of additionalagents include antibiotics (e.g. Aminoglycosides, Cephalosporins,Chloramphenicol, Clindamycin, Erythromycins, Fluoroquinolones,Macrolides, Azolides, Metronidazole, Penicillin's, Tetracycline's,Trimethoprim-sulfamethoxazole, Vancomycin), steroids (e.g. Andranes(e.g. Testosterone), Cholestanes (e.g. Cholesterol), Cholic acids (e.g.Cholic acid), Corticosteroids (e.g. Dexamethasone), Estraenes (e.g.Estradiol), Pregnanes (e.g. Progesterone), narcotic and non-narcoticanalgesics (e.g. Morphine, Codeine, Heroin, Hydromorphone, Levorphanol,Meperidine, Methadone, Oxydone, Propoxyphene, Fentanyl, Methadone,Naloxone, Buprenorphine, Butorphanol, Nalbuphine, Pentazocine),chemotherapy (e.g. anti-cancer drugs such as but not limited toAltretamine, Asparaginase, Bleomycin, Busulfan, Carboplatin, Carmustine,Chlorambucil, Cisplatin, Cladribine, Cyclophosphamide, Cytarabine,Dacarbazine, Diethyl stilbesterol, Ethinyl estradiol, Etoposide,Floxuridine, Fludarabine, Fluorouracil, Flutamide, Goserelin,Hydroxyurea, Idarubicin, Ifosfamide, Leuprolide, Levamisole, Lomustine,Mechlorethamine, Medroxyprogesterone, Megestrol, Melphalan,Mercaptopurine, Methotrexate, Mitomycin, Mitotane, Mitoxantrone,Paclitaxel, pentastatin, Pipobroman, Plicamycin, Prednisone,Procarbazine, Streptozocin, Tamoxifen, Teniposide, Vinblastine,Vincristine), anti-inflammatory agents (e.g. Alclofenac; AlclometasoneDipropionate; Algestone Acetonide; alpha Amylase; Amcinafal; Amcinafide;Amfenac Sodium; Amiprilose Hydrochloride; Anakinra; Anirolac;Anitrazafen; Apazone; Balsalazide Disodium; Bendazac; Benoxaprofen;Benzydamine Hydrochloride; Bromelains; Broperamole; Budesonide;Carprofen; Cicloprofen; Cintazone; Cliprofen; Clobetasol Propionate;Clobetasone Butyrate; Clopirac; Cloticasone Propionate; CormethasoneAcetate; Cortodoxone; Decanoate; Deflazacort; Delatestryl;Depo-Testosterone; Desonide; Desoximetasone; Dexamethasone Dipropionate;Diclofenac Potassium; Diclofenac Sodium; Diflorasone Diacetate;Diflumidone Sodium; Diflunisal; Difluprednate; Diftalone; DimethylSulfoxide; Drocinonide; Endrysone; Enlimomab; Enolicam Sodium;Epirizole; Etodolac; Etofenamate; Felbinac; Fenamole; Fenbufen;Fenclofenac; Fenclorac; Fendosal; Fenpipalone; Fentiazac; Flazalone;Fluazacort; Flufenamic Acid; Flumizole; Flunisolide Acetate; Flunixin;Flunixin Meglumine; Fluocortin Butyl; Fluorometholone Acetate;Fluquazone; Flurbiprofen; Fluretofen; Fluticasone Propionate;Furaprofen; Furobufen; Halcinonide; Halobetasol Propionate; HalopredoneAcetate; Ibufenac; Ibuprofen; Ibuprofen Aluminum; Ibuprofen Piconol;Ilonidap; Indomethacin; Indomethacin Sodium; Indoprofen; Indoxole;Intrazole; Isoflupredone Acetate; Isoxepac; Isoxicam; Ketoprofen;Lofemizole Hydrochloride; Lomoxicam; Loteprednol Etabonate;Meclofenamate Sodium; Meclofenamic Acid; Meclorisone Dibutyrate;Mefenamic Acid; Mesalamine; Meseclazone; Mesterolone;Methandrostenolone; Methenolone; Methenolone Acetate; MethylprednisoloneSuleptanate; Morniflumate; Nabumetone; Nandrolone; Naproxen; NaproxenSodium; Naproxol; Nimazone; Olsalazine Sodium; Orgotein; Orpanoxin;Oxandrolane; Oxaprozin; Oxyphenbutazone; Oxymetholone; ParanylineHydrochloride; Pentosan Polysulfate Sodium; Phenbutazone SodiumGlycerate; Pirfenidone; Piroxicam; Piroxicam Cinnamate; PiroxicamOlamine; Pirprofen; Prednazate; Prifelone; Prodolic Acid; Proquazone;Proxazole; Proxazole Citrate; Rimexolone; Romazarit; Salcolex;Salnacedin; Salsalate; Sanguinarium Chloride; Seclazone; Sermetacin;Stanozolol; Sudoxicam; Sulindac; Suprofen; Talmetacin; Talniflumate;Talosalate; Tebufelone; Tenidap; Tenidap Sodium; Tenoxicam; Tesicam;Tesimide; Testosterone; Testosterone Blends; Tetrydamine; Tiopinac;Tixocortol Pivalate; Tolmetin; Tolmetin Sodium; Triclonide;Triflumidate; Zidometacin; Zomepirac Sodium), or anti-histaminic agents(e.g. Ethanolamines (like diphenhydrmine carbinoxamine), Ethylenediamine(like tripelennamine pyrilamine), Alkylamine (like chlorpheniramine,dexchlorpheniramine, brompheniramine, triprolidine), otheranti-histamines like astemizole, loratadine, fexofenadine,Bropheniramine, Clemastine, Acetaminophen, Pseudoephedrine,Triprolidine).

EXAMPLES

Preparative thin layer chromatography (PTLC) separations describedherein were typically performed on 20×20 cm plates (500 micron thicksilica gel).

Chromatographic purifications were typically performed using BiotageIsolera One automated systems running Biotage Isolera One 2.0.6 software(Biotage LLC, Charlotte, N.C.). Flow rates were the default valuesspecified for the particular column in use. Reverse phase chromatographywas performed using elution gradients of water and acetonitrile onKP-C18-HS Flash+ columns (Biotage LLC) of various sizes. Typical loadingwas between 1:50 and 1:1000 crude sample:RP SiO₂ by weight. Normal phasechromatography was performed using elution gradients of various solvents(e.g. hexane, ethyl acetate, methylene chloride, methanol, acetone,chloroform, MTBE, etc.). The columns were SNAP Cartridges containingKP-SIL or SNAP Ultra (25 μm spherical particles) of various sizes(Biotage LLC). Typical loading was between 1:10 to 1:150 crudesample:SiO₂ by weight. Alternatively, silica gel chromatography wasperformed on a Biotage Horizon flash chromatography system.

¹H NMR analyses of intermediates and exemplified compounds weretypically performed on an Agilent Technologies 400/54 or Bruker Ascend™400 spectrometer (operating at 400 MHz) at 298° K following standardoperating procedure suggested by manufacturer. Reference frequency wasset using TMS as an internal standard. Typical deuterated solvents wereutilized as indicated in the individual examples.

LCMS analysis were typically performed using one of the two conditionslisted below:

(1) LCMS spectra were taken on an Agilent Technologies 1260 Infinitycoupled to 6120 Quadrupole spectrometer. The mobile phase for the LC wasacetonitrile (A) and water (B) with 0.01% formic acid, and the eluentgradient was from 5-95% A in 6.0 min, 60-95% A in 5.0 min, 80-100% A in5.0 min and 85-100% A in 10 min using a SBC18 50 mm×4.6 mm×2.7 μmcapillary column. Mass spectra (MS) were measured by electrosprayion-mass spectroscopy (ESI). All temperatures are in degrees Celsiusunless otherwise noted.

(2) LCMS analysis of intermediates and exemplified compounds wasperformed on an Agilent Technologies 1200 Series HPLC system coupled toan Agilent Technologies 6150 Quadrapole LC/MS detector. Analytes weredetected by UV absorbance at 220 and 254 nm. Analyte ions were detectedby mass spectrometry in both negative and positive modes (110-800 amuscan range, API-ES ionization). A long HPLC method was run on aPhenomenex® Kinetex 2.6μ C18 100 Å, 30×3.00 mm column. The columntemperature was set at 40° C. UV absorptions were detected at 220 and254 nm. Samples were prepared as a solution in about 1:1 (v/v)acetonitrile:water mixture. Flow rate was about 0.80 mL/minute. Elutionsolvents were acetonitrile and water each containing 0.1% formic acid.In a typical run, a linear gradient starting with 5% acetonitrile and95% water and ending with 95% acetonitrile and 5% water over 12 minuteswas carried out. At the end of each run, the column was washed with 95%acetonitrile and 5% water for 2 minutes.

Typically, analytical HPLC mass spectrometry conditions were as follows:

LC1: Column: SB-C18 50 mm×4.6 mm×2.7 am; Temperature: 50° C.; Eluent:5:95 v/v acetonitrile/water+0.01% formic acid in 6 min; Flow Rate: 1.5mL/min; Injection 5 μL; Detection: PDA, 200-600 nm; MS: mass range150-750 amu; positive ion electrospray ionization.

LC2: Column: SB-C18 50 mm×4.6 mm×2.7 am; Temperature: 50° C.; Eluent:5:95 to 95:5 v/v acetonitrile/water+0.05% TFA over 3.00 min; Flow Rate:1.5 mL/min; Injection 5 μL; Detection: PDA, 200-600 nm; MS: mass range150-750 amu; positive ion electrospray ionization.

LC3: Column: SB-C18 50 mm×4.6 mm×2.7 am; Temperature: 50° C.; Eluent:10:90 to 98:2 v acetonitrile/water+0.05% TFA over 3.75 min; Flow Rate:1.0 mL/min; Injection 10 μL; Detection: PDA, 200-600 nm; MS: mass range150-750 amu; positive ion electrospray ionization.

Preparative HPLC were carried out with one of the two conditions listedbelow:

Condition 1: GILSON Preparative HPLC System; Column: SHISEIDO CAPCELLPAK, MG; C18, 20 mm×250 mm, 5 μm; Mobile phase: Water+0.1%trifluoroacetic acid; ACN+0.1% trifluoroacetic acid; Method: 15 minutesgradient elution; Initial organic: 10%; Final organic: 80%; UV1: 240;UV2: 230; Flow: 15 ml/min.

Condition 2: GILSON Preparative HPLC System; Column: SunFire® Prep C18OBD™ 5 uM, 19 mm×150 mm; Mobile phase: Water+0.1% trifluoroacetic acid;ACN+0.1% trifluoroacetic acid; Method: 20 minutes gradient elution;Initial organic: 10%; Final organic: 80%; UV1: 220; UV2: 254; Flow: 15ml/min.

Compound names were generated with ChemDraw Professional 15.1 or OpenEyeScientific Software's mol2nam application.

Example 1: Synthesis of[(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(1-phenylethylamino)purin-9-yl]tetrahydrofuran-2-yl]methoxymethylphosphonicacid (Compound 18)

Step A: A mixture of((3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(1.09 g, 3.34 mmol), (diethoxyphosphoryl)methyl 4-methylbenzenesulfonate(1.29 g, 4.0 mmol) and magnesium 2-methylpropan-2-olate (0.74 g, 4.34mmol) in DMSO (15 mL) was stirred at 50° C. for 18 hours. After coolingto ambient temperature, water (10 mL) and 1:1 MTBE/ethyl acetate (20 mL)were added. The mixture was passed through a short pad of celite. Theorganic layer was separated, washed with brine, dried (sodium sulfate),filtered and concentrated under reduced pressure. The residue obtainedwas purified by flash chromatography on silica gel 10:1 ethylacetate/methanol to give diethyl((((3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(1.27 g, 80%) as solid. LCMS ESI (+) m/z 477 (M+H)

Step B: 1-Phenylethyl amine (80.0 mg, 0.66 mmol) was added to diethyl((((3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(40.0 mg, 0.08 mmol) in absolute ethanol (2 mL). The mixture was stirredat 45° C. overnight. The mixture was concentrated under reduced pressureand purified by preparative TLC to give diethyl((((3aR,4R,6R,6aR)-2,2-dimethyl-6-(6-((1-phenylethyl)amino)-9H-purin-9-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(40 mg, 85%).

Step C: To a mixture of diethyl((((3aR,4R,6R,6aR)-2,2-dimethyl-6-(6-((1-phenylethyl)amino)-9H-purin-9-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(40.0 mg, 0.07 mmol) in dichloromethane (4 mL) were added 2,6-Lutidine(160.0 mg, 1.49 mmol) and bromotrimethylsilane (240.0 mg, 1.57 mmol).The reaction mixture was stirred at room temperature overnight. Thereaction mixture was concentrated under reduced pressure. The residuewas co-evaporated with MeCN twice, then purified by reverse phase HPLC(0.1% HCOOH, 25% to 65% MeCN/H₂O over 15 min) to give the product((((3aR,4R,6R,6aR)-2,2-dimethyl-6-(6-((1-phenylethyl)amino)-9H-purin-9-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonicacid (28.0 mg, 78%) as solid.

Step D: A solution of[(3aR,4R,6R,6aR)-2,2-dimethyl-4-[6-(1-phenylethylamino)purin-9-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxymethylphosphonicacid (28.0 mg, 0.06 mmol) in 80% HCOOH aqueous solution (3 mL) wasstirred at ambient temperature for 2 hours. The mixture was concentratedunder reduced pressure and the residue obtained was purified by reversephase HPLC (0.1% HCOOH, 20 to 60% MeCN/H₂O over 15 min) to afford[(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(1-phenylethylamino)purin-9-yl]tetrahydrofuran-2-yl]methoxymethylphosphonicacid (20.0 mg, 78%) as solid. LCMS ESI (−) m/z 464 (M−H)

Example 2: Synthesis of[(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-isopropoxypurin-9-yl)tetrahydrofuran-2-yl]methoxymethylphosphonicacid (Compound 44)

Step A: To a solution of 2-Propanol (5 mL) was added 60% NaH (12.6 mg,0.31 mmol) at 0° C. After 30 min at 0° C., diethyl((((3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(40.0 mg, 0.08 mmol) was added. The reaction mixture was stirred at 0°C. for 0 minutes, water (10 mL) and ethyl acetate (10 mL) were added.The organic layer was separated, dried (sodium sulfate), filtered andconcentrated under reduced pressure. The residue obtained was purifiedby column chromatography on silica gel to give diethyl((((3aR,4R,6R,6aR)-6-(6-isopropoxy-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(33 mg, 63%) as oil.

Step B: To a solution of diethyl diethyl((((3aR,4R,6R,6aR)-6-(6-isopropoxy-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(33 mg, 0.05 mmol), 2,6-Lutidine (113 mg, 1.05 mmol) in dichloromethane(2 mL) was added bromotrimethylsilane (161.5 mg, 1.05 mmol). Thereaction mixture was stirred at room temperature overnight. The reactionmixture was concentrated under reduced pressure. The residue wasco-evaporated with MeCN twice to give[(3aR,4R,6R,6aR)-4-(6-isopropoxypurin-9-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxymethylphosphonicacid (40 mg) which was used directly in the next step.

Step C: A solution of[(3aR,4R,6R,6aR)-4-(6-isopropoxypurin-9-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxymethylphosphonicacid (40 mg) in 80% HCOOH aqueous solution (3 mL) was stirred at ambienttemperature for 2 hours. The mixture was concentrated under reducedpressure and the residue obtained was purified by reverse phase HPLC(0.1% HCOOH, 20 to 60% MeCN/H₂O over 15 min) to afford[(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-isopropoxypurin-9-yl)tetrahydrofuran-2-yl]methoxymethylphosphonicacid (9 mg, 82%) as solid. LCMS ESI (−) m/z 403 (M−H)

Example 3: Synthesis of[(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-phenylpurin-9-yl)tetrahydrofuran-2-yl]methoxymethylphosphonicacid (Compound 46)

Step A: A mixture of diethyl((((3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(0.05 g, 0.10 mmol), Phenylboronic acid (0.03 g, 0.21 mmol) andDichloro[1;1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.01 g, 0.01 mmol) in 1,4-Dioxane (2 mL) andWater (0.50 mL) was stirred at 100° C. for 8 hours. After cooled toambient temperature, water (10 mL) and 1:1 MTBE/ethyl acetate (20 mL)were added. The mixture was passed through a short pad of celite. Theorganic layer was separated, washed with brine, dried (sodium sulfate),filtered and concentrated under reduced pressure. The residue obtainedwas purified by reverse phase purification (Biotage Isolera One unit,Biotage@SNAP Ultra C18 30 g column, 20-90% CH₃CN/water, 10 CV) to givediethyl((((2R,3S,4R,5R)-3,4-dihydroxy-5-(6-phenyl-9H-purin-9-yl)tetrahydrofuran-2-yl)methoxy)methyl)phosphonate(0.034 g, 62%) as oil. LCMS ESI (+) m/z 519 (M+H)

Step B: To a solution of diethyl((((2R,3S,4R,5R)-3,4-dihydroxy-5-(6-phenyl-9H-purin-9-yl)tetrahydrofuran-2-yl)methoxy)methyl)phosphonate(0.03 g, 0.07 mmol) in Dichloromethane (2 mL) was added 2,6-Lutidine(0.04 mL, 0.33 mmol) and trimethyl bromosilane (0.04 mL, 0.33 mmol) atambient temperature. The reaction mixture was stirred at thistemperature for 5 hours. The reaction mixture was concentrated underreduced pressure. The residue was co-evaporated with methanol threetimes to give a light yellow solid. Formic acid (80% v/v) (2 mL) wasadded. The reaction mixture was stirred at ambient temperature for 3hours. Solvent was removed under reduced pressure. The residue waspurified by reverse phase HPLC (5-60% CH₃CN/water (0.1% TFA)) to give[(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-phenylpurin-9-yl)tetrahydrofuran-2-yl]methoxymethylphosphonicacid (0.024 g, 68%) as TFA salts. LCMS ESI (−) m/z 421 (M−H).

Example 4: Synthesis of((((2R,3S,4R,5R)-5-(2-chloro-6-(((S)-1-phenylethyl)amino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonicacid (Compound 21)

Step A: A mixture of[(3aR,4R,6R,6aR)-4-(2,6-dichloropurin-9-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol(0.21 g, 0.57 mmol) and N, N-Diisopropylethylamine (0.15 mL, 0.85 mmol)in 2-propanol (2 mL) was added (S)-(−)-1-Phenylethylamine (0.09 g, 0.74mmol) at ambient temperature. The mixture was stirred at ambienttemperature for 18 hours. Water (20 mL) and ethyl acetate (10 mL) wereadded. The organic layer was separated, washed with brine, dried (sodiumsulfate), filtered and concentrated under reduced pressure. The residueobtained was purified by flash chromatography on silica gel ethylacetate to give [(3aR,4R,6R,6aR)-4-[2-chloro-6-[[(1S)-1-phenylethyl]amino]purin-9-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol(0.25 g, 98% yield) as solid. LCMS ESI (+) m/z 446 (M+H)

Step B: A mixture of [(3aR,4R,6R,6aR)-4-[2-chloro-6-[[(1S)-1-phenylethyl]amino]purin-9-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol(0.25 g, 0.56 mmol), diethoxyphosphoryl)methyl 4-methylbenzenesulfonate(0.27 g, 0.84 mmol) and magnesium 2-methylpropan-2-olate (0.21 g, 1.23mmol) in Dimethyl sulfoxide (4 mL) was stirred at 50° C. for 18 hours.After cooled to ambient temperature, water (10 mL) and 1:1 MTBE/ethylacetate (20 mL) were added. The mixture was passed through a short padof celite. The organic layer was separated, washed with brine, dried(sodium sulfate), filtered and concentrated under reduced pressure. Theresidue obtained was purified by flash chromatography on silica gel 10:1ethyl acetate/methanol to give diethyl((((3aR,4R,6R,6aR)-6-(2-chloro-6-(((S)-1-phenylethyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(0.22 g, 65%) as solid. LCMS ESI (+) m/z 596 (M+H)

Step C: To a solution of((((3aR,4R,6R,6aR)-6-(2-chloro-6-(((S)-1-phenylethyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(0.07 g, 0.12 mmol) in Dichloromethane (3 mL) was added 2,6-Lutidine(0.07 mL, 0.61 mmol) and bromotrimethylsilane (0.08 mL, 0.61 mmol) atambient temperature. The reaction mixture was stirred at thistemperature for 18 hours. The reaction mixture was concentrated underreduced pressure. The residue was co-evaporated with methanol threetimes to give a light yellow solid. It was dissolved in 80% formic acid(1 mL) and stirred at ambient temperature for 6 hours. The reactionmixture was concentrated under reduced pressure. The residue wasdissolved in water (0.5 mL) and Lithium hydroxide monohydrate (1.79 mg,0.04 mmol) was added. It was stirred at ambient temperature for 2 hours.It was purified directly by preparative reverse phase HPLC (10-80%CH₃CN/water (0.1% TFA)) to give((((2R,3S,4R,5R)-5-(2-chloro-6-(((S)-1-phenylethyl)amino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonicacid (0.022 g, 36% yield) as TFA salt. LCMS ESI (−) m/z 498 (M−H).

Example 5: Synthesis of [(2R,3S,4R,5R)-5-[2-cyano-6-[[(1S)-1-phenylethyl]amino]purin-9-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonicacid; 2,2,2-trifluoroacetic acid (Compound 36)

Step A: A mixture of((((3aR,4R,6R,6aR)-6-(2-chloro-6-(((S)-1-phenylethyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(0.16 g, 0.27 mmol) and Sodium Cyanide (0.07 g, 1.33 mmol) in Dimethylsulfoxide (2 mL) was heated at Microwave at 150° C. for 1 hour and 170°C. for another hour. It was directly purified by reverse phase column(Biotage Isolera One unit, Biotage@SNAP Ultra C18 60 g column, 0-100%CH₃CN/water, 10 CV) to give [(3aR,4R,6R,6aR)-4-[2-cyano-6-[[(1S)-1-phenylethyl]amino]purin-9-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxymethyl-ethoxy-phosphinicacid (0.064 g, 43% yield) as solid. LCMS ESI (+) m/z 559 (M+H)

Step B: To a solution of[(3aR,4R,6R,6aR)-4-[2-cyano-6-[[(1S)-1-phenylethyl]amino]purin-9-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxymethyl-ethoxy-phosphinicacid (0.06 g, 0.11 mmol) in Dichloromethane (3 mL) was added2,6-Lutidine (0.07 mL, 0.57 mmol) and bromotrimethylSilane (0.08 mL,0.57 mmol) at ambient temperature. The reaction mixture was stirred atthis temperature for 18 hours. The reaction mixture was concentratedunder reduced pressure. The residue was co-evaporated with methanolthree times to give a light yellow solid. Formic acid (80% v/v) (2 mL)was added. The reaction mixture was stirred at ambient temperature for 3hours. Solvent was removed under reduced pressure. The residue waspurified by preparative reverse phase HPLC (10-80% CH₃CN/water (0.1%TFA)) to give[(2R,3S,4R,5R)-5-[2-cyano-6-[[(1S)-1-phenylethyl]amino]purin-9-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonicacid; 2,2,2-trifluoroacetic acid (0.041 g, 59%) as TFA salt. LCMS ESI(−) m/z 489 (M−H).

Example 6: Synthesis of[(2R,3S,4R,5R)-5-[6-(benzylamino)-2-phenyl-purin-9-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonicacid (Compound 8)

Step A: A mixture of diethyl((((3aR,4R,6R,6aR)-6-(6-(benzylamino)-2-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(0.05 g, 0.16 mmol), Phenylboronic acid (0.02 g, 0.17 mmol) andDichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.01 g, 0.01 mmol) in 1,4-Dioxane (2 mL) andwater (0.50 mL) was stirred at 100° C. for 8 hours. After cooled toambient temperature, water (10 mL) and 1:1 MTBE/ethyl acetate (20 mL)were added. The mixture was passed through a short pad of celite. Theorganic layer was separated, washed with brine, dried (sodium sulfate),filtered and concentrated under reduced pressure. The residue obtainedwas purified by flash chromatography on silica gel 10:1 ethylacetate/methanol to give diethyl((((3aR,4R,6R,6aR)-6-(6-(benzylamino)-2-phenyl-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(0.048 g, 89%) as solid. LCMS ESI (+) m/z 624 (M+H)

Step B: A mixture of diethyl((((3aR,4R,6R,6aR)-6-(6-(benzylamino)-2-phenyl-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(0.05 g, 0.08 mmol) and 2,6-Lutidine (0.09 mL, 0.77 mmol) inDichloromethane (2 mL) was added bromotrimethylsilane (0.1 mL, 0.77mmol) at ambient temperature and stirred at room temperature for 18hours. The reaction mixture was concentrated under reduced pressure. Theresidue was co-evaporated with methanol three times to give a lightyellow solid. 80% formic acid (3 mL) was added and stirred at ambienttemperature for 4 hours. Formic acid was removed under reduced pressure.The residue obtained was added 5 mL of saturated sodium bicarbonate andMTBE (10 mL). The aqueous layer was separated and was purified byreverse phase column (Biotage Isolera One unit, Biotage@SNAP Ultra C1860 g column, 0-80% CH₃CN/water, 10 CV) to give[(2R,3S,4R,5R)-5-[6-(benzylamino)-2-phenyl-purin-9-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonicacid (0.016 g, 39%) as sodium salts. LCMS ESI (−) m/z 526 (M−H).

Example 7: Synthesis of[(2R,3S,4R,5R)-5-[2-chloro-4-[[(1R)-1-phenylethyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonicacid (Compound 61)

Step A: To a solution of[(3aR,4R,6R,6aR)-4-(2,4-dichloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol(0.12 g, 0.33 mmol) in n-butanol (5 mL) was added(R)-(+)-1-Phenylethylamine (0.081 g, 0.67 mmol) and TEA (0.067 g, 0.66mmol). The mixture was stirred at 100° C. for 16 hours, the solvent wasremoved under reduced pressure; the residue was partitioned betweenwater and Ethyl acetate. The organic layer was separated, dried (sodiumsulfate), filtered and concentrated under reduced pressure. The residueobtained was purified by column chromatography on silica gel 1:1petroleum ether/ethyl acetate to give[(3aR,4R,6R,6aR)-4-[2-chloro-4-[[(1R)-1-phenylethyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol(0.13 g, 89%). LCMS ESI (+) m/z 445 (M+H)

Step B: To a solution of[(3aR,4R,6R,6aR)-4-[2-chloro-4-[[(1R)-1-phenylethyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol(0.13 g, 0.30 mmol) in 1-Methyl-2-pyrrolidone (5 mL) was added 60%sodium hydride (0.060 g, 1.5 mmol) at 10° C., after 5 minutes,(diethoxyphosphoryl)methyl 4-methylbenzenesulfonate (0.19 g, 0.59 mmol)was added, the mixture was stirred at 10° C. for 30 minutes, Ethylacetate (10 mL) was added, the mixture was cooled to −5° C., thensaturated ammonium chloride solution was added. The organic layer wasseparated, dried (sodium sulfate), filtered and concentrated underreduced pressure. The residue obtained was purified by Preparative TLC(1:3 petroleum ether/ethyl acetate) to give diethyl((((3aR,4R,6R,6aR)-6-(2-chloro-6-(((R)-1-phenylethyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(0.045 g, 25%) as solid.

Step C: To a solution of((((3aR,4R,6R,6aR)-6-(2-chloro-6-(((R)-1-phenylethyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(0.020 g, 0.03 mmol) and 2,6-Lutidine (0.12 g, 1.12 mmol) inDichloromethane (4 mL) was added bromotrimethylsilane (0.18 g, 1.18mmol) at ambient temperature. The mixture was stirred at ambienttemperature overnight. The mixture was concentrated under reducedpressure. The residue was co-evaporated with CH₃CN twice to give[(3aR,4R,6R,6aR)-4-[2-chloro-4-[[(1R)-1-phenylethyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxymethylphosphonicacid which was used directly in the next step without purification.

Step D: A solution of[(3aR,4R,6R,6aR)-4-[2-chloro-4-[[(1R)-1-phenylethyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxymethylphosphonicacid (0.22 g, 0.04 mmol) in 80% HCOOH (3 mL) was stirred at ambienttemperature for 2 hours. The mixture was concentrated under reducedpressure. The residue obtained was purified by reverse phase HPLC (0.1%HCOOH, 20 to 80% MeCN/H₂O over 15 min) to give[(2R,3S,4R,5R)-5-[2-chloro-4-[[(1R)-1-phenylethyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonicacid (0.006 g, 30%) as solid. LCMS ESI (−) m/z 497 (M−H).

Example 8: Synthesis of[(2R,3S,4R,5R)-5-[2-cyano-4-[[(1R)-1-phenylethyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonicacid (Compound 62)

Step A: To a solution of7-[(3aR,4R,6R,6aR)-6-(diethoxyphosphorylmethoxymethyl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2-chloro-N-[(1R)-1-phenylethyl]pyrrolo[2,3-d]pyrimidin-4-amine(0.025 g, 0.04 mmol) in 1-Methyl-2-pyrrolidone (3 mL) was added Zn(CN)₂(0.023 g, 0.2 mmol) and Pd(PPh₃)₄ (0.046 g, 0.04 mmol) under N₂. It wasstirred at 180° C. in microwave for 2 hours. The mixture was passedthrough a pad of celite, washed with ethyl acetate. Water was added; theorganic layer was separated, dried (sodium sulfate), filtered andconcentrated under reduced pressure. The residue obtained was purifiedby preparative TLC (1:3 petroleum ether/ethyl acetate) to give7-[(3aR,4R,6R,6aR)-6-(diethoxyphosphorylmethoxymethyl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-4-[[(1R)-1-phenylethyl]amino]pyrrolo[2,3-d]pyrimidine-2-carbonitrile(0.003 g, 13%).

Step B: To a solution of7-[(3aR,4R,6R,6aR)-6-(diethoxyphosphorylmethoxymethyl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-4-[[(1R)-1-phenylethyl]amino]pyrrolo[2,3-d]pyrimidine-2-carbonitrile(0.016 g, 0.03 mmol) and 2,6-Lutidine (0.12 g, 1.12 mmol) inDichloromethane (3 mL) was added bromotrimethylsilane (0.18 g, 1.18mmol) at ambient temperature. The mixture was stirred at ambienttemperature overnight. The mixture was concentrated under reducedpressure. The residue was co-evaporated with CH₃CN twice to give[(3aR,4R,6R,6aR)-4-[2-cyano-4-[[(1R)-1-phenylethyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxymethylphosphonicacid which was used directly in the next step without purification.

Step C: To a solution of[(3aR,4R,6R,6aR)-4-[2-cyano-4-[[(1R)-1-phenylethyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxymethylphosphonicacid (0.018 g, 0.04 mmol) in 80% HCOOH (3 mL) was stirred at ambienttemperature for 2 hours. The mixture was concentrated under reducedpressure. The residue obtained was purified by reverse phase HPLC (0.1%HCOOH, 20 to 80% MeCN/H₂O over 15 min) to give[(2R,3S,4R,5R)-5-[2-cyano-4-[[(1R)-1-phenylethyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonicacid (0.003 g, 18%) as solid. LCMS ESI (−) m/z 488 (M−H).

Example 9: Synthesis of((((2R,3S,4R,5R)-5-(2-chloro-5-fluoro-4-(((S)-1-phenylethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonicacid (Compound 76)

Step A: A mixture of 2,4-dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine(0.44 g, 2.14 mmol) and N, N-Diisopropylethylamine (0.57 mL, 3.2 mmol)in s-Butanol (5 mL) was added (S)-(−)-1-Phenylethylamine (0.34 g, 2.78mmol) at ambient temperature. The mixture was stirred at reflux for 3hours. Solvent was removed under reduced pressure. The residue obtainedwas purified by flash chromatography on silica gel 1:1 hexane/ethylacetate to give2-chloro-5-fluoro-N-[(1S)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(0.45 g, 72% yield) as solid. LCMS ESI (+) m/z 291 (M+H)

Step B: To a solution of(3aR,6R,6aR)-6-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-ol(0.76 g, 2.5 mmol) and Carbon tetrachloride (0.27 mL, 2.75 mmol) inTetrahydrofuran (6 mL) was addedN,N,N′,N′,N″,N″-hexamethylphosphanetriamine (0.5 mL, 2.75 mmol) at −30°C. After addition, the mixture was stirred at −30° C. for 1 hour. It wasadded to a stirred suspension of2-chloro-5-fluoro-N-[(1S)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(0.44 g, 1.51 mmol), powdered Potassium Hydroxide (0.17 g, 3.03 mmol)and Tris[2-(2-methoxyethoxy)ethyl]amine (0.58 mL, 0.82 mmol) inAcetonitrile (12 mL) at 0° C. After addition, the reaction mixture waswarned to ambient temperature and stirred at ambient temperature for 18hours. Saturated ammonium chloride solution (50 mL) and MTBE (50 mL)were added. The organic layer was separated, washed with brine, dried(sodium sulfate), filtered and concentrated under reduced pressure. Theresidue obtained was purified by flash chromatography on silica gel 5:1hexane/ethyl acetate to give an oil. It was dissolved in THF (6 mL) andTriethylamine trihydrofluoride (1.23 mL, 7.57 mmol) was added at ambienttemperature. The reaction mixture was stirred at ambient temperature for18 hours. Solvent was removed under reduced pressure. The residueobtained was purified by flash chromatography on silica gel 3:1DCM/ethyl acetate to give [(3aR,4R,6R,6aR)-4-[2-chloro-5-fluoro-4-[[(1S)-1-phenylethyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol(0.29 g, 41% yield) as oil. LCMS ESI (+) m/z 463 (M+H)

Step C: A mixture of diisopropyl (bromomethyl)phosphonate (0.18 g, 0.39mmol) and [(3aR,4R,6R,6aR)-4-[2-chloro-5-fluoro-4-[[(1S)-1-phenylethyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol(0.10 g, 0.22 mmol) in 1-Methyl-2-pyrrolidone (2 mL) was added 60%Sodium hydride (0.020 g, 0.48 mmol) at ambient temperature. The reactionmixture was stirred at this temperature for 2 hours. 0.5 mL of water wasadded. It was purified directly by reverse phase column (Biotage IsoleraOne unit, Biotage@SNAP Ultra C18 30 g column, 20-100% CH₃CN/water, 10CV) to give diisopropyl((((3aR,4R,6R,6aR)-6-(2-chloro-5-fluoro-4-(((S)-1-phenylethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(0.13 g, 95%) as solid. LCMS ESI (+) m/z 641 (M+H)

Step D: To a solution of diisopropyl((((3aR,4R,6R,6aR)-6-(2-chloro-5-fluoro-4-(((S)-1-phenylethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(0.13 g, 0.21 mmol) in Dichloromethane (2 mL) was added 2,6-Lutidine(0.25 mL, 2.12 mmol) and bromotrimethylsilane (0.28 mL, 2.12 mmol) atambient temperature. The reaction mixture was stirred at thistemperature for 18 hours. The reaction mixture was concentrated underreduced pressure. The residue was co-evaporated with methanol threetimes to give a light yellow solid. 80% formic acid (2 mL) was added.The mixture was stirred at ambient temperature for 6 hours. The mixturewas concentrated at reduced pressure and co-evaporated with methanolthree times to give a thick oil. It was purified by preparative HPLC(10%-95% ACN/H₂O, 0.1% TFA) to give((((2R,3S,4R,5R)-5-(2-chloro-5-fluoro-4-(((S)-1-phenylethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonicacid (0.05 g, 37%) as TFA salts. LCMS ESI (−) m/z 515 (M−H).

Example 10: Synthesis of[(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonicacid (Compound 70)

Step A: A mixture of[(3aR,4R,6R,6aR)-4-(2,4-dichloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol(0.64 g, 1.78 mmol), diethoxy phosphoryl methyl 4-methylbenzenesulfonate(0.86 g, 2.67 mmol) and magnesium 2-methylpropan-2-olate (0.61 g, 3.55mmol) in Dimethyl Sulfoxide (10 mL) was heated at 70° C. under nitrogenfor 6 hours. After cooled to ambient temperature, the reaction mixturewas diluted with saturated ammonium chloride solution (30 mL) and ethylacetate (30 mL). The organic layer was separated, washed with brine,dried (sodium sulfate), filtered and concentrated under reducedpressure. The residue obtained was purified by reverse phase column(Biotage Isolera One unit, Biotage@SNAP Ultra C18 120 g column, 30-100%CH₃CN/water, 10 CV) to give diethyl((((3aR,4R,6R,6aR)-6-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(0.30 g, 33%) as solid. LCMS ESI (+) m/z 510 (M+H)

Step B: A mixture of Cyclopentanamine (0.1 g, 1.2 mmol), Et₃N (0.17 mL,1.2 mmol) and((((3aR,4R,6R,6aR)-6-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(0.31 g, 0.60 mmol) in s-Butanol (5 mL) was stirred at 100° C.overnight. The reaction mixture was concentrated. The residue waspurified by flash column chromatography with 1:1 hexane/ethyl acetate togive diethyl((((3aR,4R,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(0.30 g, 89%) as solid. LCMS ESI (+) m/z 559 (M+H)

Step C: To a solution of diethyl((((3aR,4R,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(0.31 g, 0.55 mmol) in Dichloromethane (5 mL) was added 2,6-Lutidine(0.32 mL, 2.73 mmol) and bromotrimethylsilane (0.36 mL, 2.73 mmol) atambient temperature. The reaction mixture was stirred at thistemperature for 18 hours. The reaction mixture was concentrated underreduced pressure. The residue was co-evaporated with methanol threetimes to give a light yellow solid. 80% formic acid (4 mL) was added.The mixture was stirred at ambient temperature for 6 hours. The mixturewas concentrated at reduced pressure and co-evaporated with methanolthree times to give a thick oil. 1 N NaOH (4 mL) and MTBE (20 mL) wereadded. The aqueous phase was isolated and purified directly by reversephase column (Biotage Isolera One unit, Biotage@SNAP Ultra C18 60 gcolumn, 0-70% CH₃CN/water, 10 CV) to give[(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonicacid (0.24 g, 95%) as sodium salts. LCMS ESI (−) m/z 461 (M−H).

Example 11: Synthesis of[(2R,3S,4R,5R)-5-[7-(benzylamino)-5-chloro-imidazo[4,5-b]pyridin-3-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonicacid (Compound 57)

Step A: A solution of[(3aR,4R,6R,6aR)-4-(5,7-dichloroimidazo[4,5-b]pyridin-3-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol(115 mg, 0.32 mmol), Benzylamine (54.7 mg, 0.51 mmol) and TEA (64.6 mg,0.64 mmol) in NMP (6 mL) was stirred at 130° C. in microwave for 3hours. The mixture was partitioned between water and Ethyl acetate, theorganic layer was separated, dried (sodium sulfate), filtered andconcentrated under reduced pressure. The residue obtained was purifiedby Preparative TLC to give[(3aR,4R,6R,6aR)-4-[7-(benzylamino)-5-chloro-imidazo[4,5-b]pyridin-3-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol(62 mg, 45%).

Step B: To a solution of[(3aR,4R,6R,6aR)-4-[7-(benzylamino)-5-chloro-imidazo[4,5-b]pyridin-3-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol(50 mg, 0.12 mmol) in NMP (3 mL) was added 60% NaH (9.6 mg, 0.24 mmol)at 10° C. After 10 minutes, diethoxyphosphoryl oxymethyl4-methylbenzenesulfonate (78.5 mg, 0.23 mmol) was added. The mixture wasstirred at 10° C. for an hour. The mixture was quenched with saturatedammonium chloride solution. The residue was partitioned between waterand Ethyl acetate, the organic layer was separated, dried (sodiumsulfate), filtered, concentrated under reduced pressure. The residueobtained was purified by Preparative TLC 20:1 DCM/MeOH to give diethyl((((3aR,4R,6R,6aR)-6-(7-(benzylamino)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(13 mg, 20%).

Step C: To a solution of diethyl((((3aR,4R,6R,6aR)-6-(7-(benzylamino)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(13 mg, 0.02 mmol) in Dichloromethane (3 mL) was added 2,6-Lutidine (60mg, 0.56 mmol) and bromotrimethylsilane(90 mg, 0.59 mmol) at ambienttemperature. The mixture was stirred at ambient temperature overnight.The mixture was concentrated under reduced pressure and the residue wasco-evaporated with CH₃CN twice to give[(3aR,4R,6R,6aR)-4-[7-(benzylamino)-5-chloro-imidazo[4,5-b]pyridin-3-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxymethylphosphonicacid which was used directly in the next step without purification.

Step D: To a solution of[(3aR,4R,6R,6aR)-4-[7-(benzylamino)-5-chloro-imidazo[4,5-b]pyridin-3-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxymethylphosphonic acid (20 mg, 0.04 mmol) in 80% HCOOH (3 mL) was stirred atambient temperature for 2 hours. The mixture was concentrated underreduced pressure. The residue obtained was purified by reverse phaseHPLC (0.1% HCOOH, 20 to 80% MeCN/H₂O over 15 min)[(2R,3S,4R,5R)-5-[7-(benzylamino)-5-chloro-imidazo[4,5-b]pyridin-3-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonicacid (3.3 mg, 17%). LCMS ESI (−) m/z 483 (M−H).

Example 12: Synthesis of[(2R,3S,4R,5R)-5-[6-chloro-4-[[(1R)-1-phenylethyl]amino]pyrrolo[2,3-b]pyridin-1-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonicacid (Compound 134)

Step A: 4,6-Dichloro-1H-pyrrolo[2,3-b]pyridine (1.0 g, 5.4 mmol) wascombined with (R)-(+)-1-phenylethylamine (5.5 mL, 43 mmol) and themixture was heated in the microwave reactor at 220° C. for 4 hours. Themixture was cooled and washed three times with 10% aqueous citric acid,water, saturated NaCl, dried over Na₂SO₄ and concentrated in vacuo. Thedark residue was slurried in methylene chloride and the undissolvedsolids were removed by filtration, washed with methylene chloride thenthe filtrate was chromatographed on SiO₂ (Biotage SNAP 25 g) and elutedwith a gradient of ethyl acetate/hexanes. Two isomeric materials elutedfrom the column. The less polar material was confirmed as the desiredproduct by NMR, (336 mg). LCMS ESI (+) m/z 272.1 (M+H).

Step B: A solution of(3aR,6R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol(0.57 g, 1.9 mmol) dissolved in a mixture of carbon tetrachloride (0.2mL, 2.1 mmol) and THF (3.3 mL) was cooled to −30° C. and treateddropwise with N,N,N,N,N,N-hexamethyl-phosphorus triamide (0.37 mL, 2.1mmol). The mixture was stirred for 1 hour at −30° C. then a portion wasused directly in the next step.

Step C: Potassium hydroxide (0.080 g, 1.5 mmol) was powdered and addedto a solution of(R)-6-chloro-N-(1-phenylethyl)-1□²-pyrrolo[2,3-b]pyridin-4-amine (0.20g, 0.74 mmol) and 3-[bis[2-(2-methoxyethoxy)ethyl]amino]propan-1-ol;1-methoxypropane (0.31 mL, 0.88 mmol) dissolved in acetonitrile (3 mL).The resulting suspension was stirred in an ambient temperature bath andtreated dropwise with a solution oftert-butyl(((3aR,4R,6aR)-6-chloro-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)dimethylsilane(0.31 g, 0.96 mmol) dissolved in THF (1.7 mL) [Step B]. The mixture wasstirred at ambient temperature for 14 hours. The reaction was quenchedwith saturated NH₄Cl (˜30 mL) and ethyl acetate. The layers wereseparated and the organic layer was washed with saturated NaCl, driedover Na₂SO₄ and concentrated in vacuo. The crude oil was chromatographedon SiO₂ (Biotage SNAP Ultra 10 g) and eluted with a gradient of ethylacetate/hexanes. Two isomeric products were eluted and the more polarone was identified as the desired product by NMR, (115 mg). LCMS ESI (+)m/z 558.3 (M+H).

Step D:1-((3aR,4R,6R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-6-chloro-N-((R)-1-phenylethyl)-1H-pyrrolo[2,3-b]pyridin-4-amine(115 mg, 0.21 mmol) was dissolved in THF (1 mL) and treated withtriethylamine trihydrofluoride (0.10 mL, 0.62 mmol). The reaction wasstirred at ambient temperature for 6 hours. The mixture was concentratedin vacuo then the crude product was chromatographed on SiO₂ (BiotageSNAP 10 g) and eluted with a gradient of ethyl acetate/hexanes, (35 mg).LCMS ESI (+) m/z 444.2 (M+H).

Step E:((3aR,4R,6R,6aR)-6-(6-chloro-4-(((R)-1-phenylethyl)amino)-1H-pyrrolo[2,3-b]pyridin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(35 mg, 0.08 mmol) was dissolved in DMSO (1.4 mL) then treated with(diethoxyphosphoryl)methyl 4-methylbenzenesulfonate (38 mg, 0.12 mmol)and magnesium di-tert-butoxide (37 mg, 0.20 mmol) then the mixture washeated to 70° C. for 14 hours. The reaction was cooled then treated witha mixture of water (5 mL), MtBE (5 mL) and ethyl acetate (5 mL) thenstirred for 10 minutes. The mixture was filtered through a pad ofcelite, then the filtrate was separated and the organic layer was washedtwice with saturated NaCl, dried over Na₂SO₄ and concentrated in vacuo.The crude product was chromatographed on SiO₂ (Biotage SNAP 10 g) andeluted with a gradient of ethyl acetate/hexanes, (32 mg). LCMS ESI (+)m/z 594.3 (M+H).

Step F: Diethyl((((3aR,4R,6R,6aR)-6-(6-chloro-4-(((R)-1-phenylethyl)amino)-1H-pyrrolo[2,3-b]pyridin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(32 mg, 0.05 mmol) was treated with a pre-mixed solution of formic acid(4 mL) and water (1 mL) then mixture was stirred for 14 hours at ambienttemperature. The reaction mixture was concentrated under a stream ofnitrogen gas then redissolved and reconcentrated from acetonitrile (˜3mL) five separate times. The resulting oil was dissolved in freshacetonitrile (0.3 mL) and treated with 2,6-lutidine (0.090 mL, 0.81mmol) then bromotrimethylsilane (0.11 mL, 0.81 mmol). The reactionmixture was partially insoluble, so additional acetonitrile (0.7 mL) wasadded and the mixture was stirred at ambient temperature for 14 hours.The mixture was quenched with MeOH (˜3 mL) and evaporated using nitrogengas three times. The crude product was dissolved in MeOH (1 mL) andchromatographed on reversed-phase HPLC [Gilson 271 system] eluting witha gradient of MeCN (modified with 0.1% TFA)/water (modified with 0.1%TFA). The desired product was concentrated using a stream of nitrogengas to reduce the volume then the remainder was lyophilized to whitepowder, (9.0 mg). LCMS ESI (+) m/z 498.1 (M+H).

Example 13: Synthesis of((((((2R,3S,4R,5R)-5-(2-chloro-4-(methyl((R)-1-phenylethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)(hydroxy)phosphoryl)oxy)methylpivalate (Compound 132) and((((((2R,3S,4R,5R)-5-(2-chloro-4-(methyl((R)-1-phenylethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropanoate) (Compound 133)

Step A: A mixture of((3aR,4R,6R,6aR)-6-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(468 mg, 1.3 mmol), phosphonic acid,P-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-, diethyl ester (628 mg, 1.95mmol) and ditert-butoxymagnesium (443 mg, 2.6 mmol) in dimethylsulfoxide (2 mL) was heated at 70° C. under nitrogen overnight. Thereaction mixture was diluted with brine and extracted with EtOAc. Theorganic layer was dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified by flash column chromatography with EtOAc/hexane(10% to 100%) followed by MeOH/EtOAc (0% to 10%) to give diethyl((((3aR,4R,6R,6aR)-6-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(92 mg, 0.18 mmol, 14% yield). LCMS ESI (+) m/z 510 (M+H).

Step B: A mixture of (R)-N-methyl-1-phenylethan-1-amine (49 mg, 0.36mmol), Et₃N (0.13 mL, 0.9 mmol) and diethyl((((3aR,4R,6R,6aR)-6-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(92 mg, 0.18 mmol) in 2-propanol (3 mL) was heated at 100° C. overnight.The reaction mixture was concentrated. The residue was purified by flashcolumn chromatography with EtOAc/hexane (10% to 100%) to give diethyl((((3aR,4R,6R,6aR)-6-(2-chloro-4-(methyl((R)-1-phenylethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(100 mg, 0.16 mmol, 91% yield). LCMS ESI (+) m/z 609 (M+H).

Step C: To a solution of diethyl((((3aR,4R,6R,6aR)-6-(2-chloro-4-(methyl((R)-1-phenylethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(77 mg, 0.13 mmol) in acetonitrile (3 mL) was added 2,6-lutidine (0.15mL, 1.26 mmol) followed by silane, bromotrimethyl- (0.17 mL, 1.26 mmol).The reaction was stirred at room temperature for 6 h and concentratedunder reduced pressure. The residue was dissolved in methanol and thenconcentrated. The process was repeated one more time. The residue waspurified by reverse phase flash column chromatography with CH3CN/water(10% to 80%) to give((((3aR,4R,6R,6aR)-6-(2-chloro-4-(methyl((R)-1-phenylethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonicacid (54 mg, 0.1 mmol, 77% yield). LCMS ESI (+) m/z 553 (M+H).

Step D: A mixture of iodomethyl 2,2-dimethylpropanoate (0.02 mL, 0.15mmol), silver oxide (Ag₂O) (45 mg, 0.2 mmol) and((((3aR,4R,6R,6aR)-6-(2-chloro-4-(methyl((R)-1-phenylethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonicacid (54 mg, 0.1 mmol) in DMF (3 mL) was stirred at 70° C. for 4 h. Thereaction mixture was directly purified by reverse phase columnchromatography with CH₃CN/water (20% to 90%) to give((((((3aR,4R,6R,6aR)-6-(2-chloro-4-(methyl((R)-1-phenylethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)(hydroxy)phosphoryl)oxy)methylpivalate (LCMS ESI (+) m/z 667 (M+H)) and((((((3aR,4R,6R,6aR)-6-(2-chloro-4-(methyl((R)-1-phenylethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropanoate) (LCMS ESI (+) m/z 781 (M+H)) (yields werenot determined; used in the next step).

Step E: A mixture of water (1 mL), formic acid (4 mL) and((((((3aR,4R,6R,6aR)-6-(2-chloro-4-(methyl((R)-1-phenylethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)(hydroxy)phosphoryl)oxy)methylpivalate (prepared in step D) was stirred at room temperature for 4 h.The reaction mixture was concentrated with a stream of nitrogen andpurified by reverse phase prep HPLC with CH₃CN/water (10% to 95% with 1%TFA) to give((((((2R,3S,4R,5R)-5-(2-chloro-4-(methyl((R)-1-phenylethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)(hydroxy)phosphoryl)oxy)methylpivalate (6.4 mg, LCMS ESI (+) m/z 627 (M+H)).

((((((2R,3S,4R,5R)-5-(2-chloro-4-(methyl((R)-1-phenylethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropanoate) (4.9 mg, LCMS ESI (+) m/z 741 (M+H)) wasprepared similarly.

Example 14: Synthesis of(((((((2S,3S,4R,5R)-5-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropanoate) (Compound 165)

Step A: A mixture of((3aR,4R,6R,6aR)-6-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(1.0 g, 2.78 mmol), triethylamine (0.58 mL, 4.16 mmol) andcyclopentanamine (0.47 g, 5.55 mmol) in 2-propanol (12 mL) was heated at85° C. overnight. Solvent was removed under reduced pressure. Theresidue was purified by flash chromatography on silica gel withhexane/ethyl acetate (10% to 100%) to give((3aR,4R,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(0.98 g, 2.4 mmol, 87% yield) as a solid. LCMS ESI (+) m/z 409 (M+H).

Step B: To a solution of thioacetic acid (0.34 mL, 4.8 mmol) and((3aR,4R,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(982 mg, 2.4 mmol) in anhydrous tetrahydrofuran (12 mL) at 0° C. wasadded triphenylphosphine (1.89 g, 7.21 mmol) followed by diisopropylazodicarboxylate (1.41 mL, 7.21 mmol). The ice bath was removed. Thereaction was stirred at room temperature overnight. Additionalthioacetic acid (0.34 mL, 4.8 mmol), triphenylphosphine (0.945, 3.6mmol) and diisopropyl azodicarboxylate (1.41 mL, 7.21 mmol) were added.The reaction mixture was stirred at room temperature for another 4 h,diluted with brine and extracted with EtOAc. The organic layer was driedover Na₂SO₄, filtered, and concentrated. The residue was purified byflash column chromatography with EtOAc/hexane (10% to 80%) to giveS-(((3aS,4S,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)ethanethioate (870 mg, 1.86 mmol, 78% yield). LCMS ESI (+) m/z 467(M+H).

Step C: A solution ofS-(((3aS,4S,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)ethanethioate (314 mg, 0.6700 mmol) in 2-propanol (10 mL) was purgedwith nitrogen for 30 minutes. Isopropoxysodium (110.38 mg, 1.34 mmol)was added. The mixture was stirred at room temperature for 30 minutes.Phosphonic acid, P-(bromomethyl)-, bis(1-methylethyl) ester (348.4 mg,1.34 mmol) was added. The reaction mixture was stirred at 60° C. for 1 hand then directly purified by flash column chromatography withEtOAc/hexane (10% to 100%) to give diisopropyl(((((3aS,4S,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)thio)methyl)phosphonate(433 mg, 0.72 mmol, quant. yield). LCMS ESI (+) m/z 603 (M+H).

Step D: To a solution of diisopropyl(((((3aS,4S,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)thio)methyl)phosphonate(280 mg, 0.46 mmol) in acetonitrile (5 mL) was added 2,6-lutidine (0.54mL, 4.64 mmol) followed by bromotrimethylsilane (0.61 mL, 4.64 mmol).The reaction mixture was stirred at room temperature for 4 h and thenconcentrated under reduced pressure. The residue was dissolved inmethanol, and then concentrated. The process was repeated one more time.The residue was purified by reverse phase flash column chromatographywith CH₃CN/water (10% to 80%) to give(((((3aS,4S,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)thio)methyl)phosphonicacid (217 mg, 0.42 mmol, 90% yield). LCMS ESI (+) m/z 519 (M+H).

Step E: A mixture of silver oxide (Ag₂O) (549 mg, 2.37 mmol),(((((3aS,4S,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)thio)methyl)phosphonicacid and propanoic acid, 2,2-dimethyl-, iodomethyl ester (0.18 mL, 1.18mmol) in N,N-dimethylformamide (6 mL) was heated at 75° C. overnight.Additional propanoic acid, 2,2-dimethyl-, iodomethyl ester (0.18 mL,1.18 mmol) was added and the reaction mixture was stirred at 70° C. for4 h. After cooling to room temperature, the mixture was diluted withEtOAc and saturated aqueous NaH₂PO₄, and filtered through celite. Theorganic layer was separated, dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by reverse phase columnchromatography with CH₃CN/water (10% to 100%) to give(((((((3aS,4S,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)thio)methyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropanoate) (98 mg, 0.13 mmol, 33% yield). LCMS ESI (+)m/z 747 (M+H).

Step F: To a solution of(((((((3aS,4S,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)thio)methyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropanoate) (0.1 g, 0.13 mmol) in acetonitrile (3 mL)and water (1 mL) was added Oxone (0.24 g, 0.79 mmol) at ambienttemperature. The mixture was stirred at ambient temperature for 5 hours.Ethyl acetate (20 mL) and water (10 mL) were added. The organic layerwas separated, washed with brine, dried (sodium sulfate), filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel with ethyl acetate/hexane (10% to 100%) togive(((((((3aS,4S,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfonyl)methyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropanoate) (0.033 g, 0.042 mmol, 32% yield, LCMS ESI(+) m/z 779 (M+H)) and (((((((3aS,4S,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfinyl)methyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropanoate) (10 mg, 0.013 mmol, 10% yield, LCMS ESI (+)m/z 763 (M+H)).

Step G: A mixture of(((((((3aS,4S,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfonyl)methyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropanoate) (0.1 g, 0.13 mmol) in water (1 mL) andformic acid (4 mL, 0.13 mmol) was stirred at ambient temperature for 3hours. The reaction mixture was concentrated with a stream of nitrogen.The residue was purified by preparative HPLC with CH₃CN/water (10% to95% with 1% TFA) to give(((((((2S,3S,4R,5R)-5-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropanoate) (0.032 g, 0.043 mmol, 33% yield). LCMS ESI(+) m/z 739 (M+H).

Example 15: Synthesis of(((((2S,3S,4R,5R)-5-(2-chloro-4-(((R)-1-(2,4-difluorophenyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonicacid (Compound 178)

Step A: A mixture of((3aR,4R,6R,6aR)-6-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(200 mg, 0.56 mmol), (1R)-1-(2,4-difluorophenyl)ethanamine (131 mg, 0.83mmol) and Et₃N (112 mg, 1.11 mmol) in n-butanol (10 mL) was stirred for24 h at 100° C. The reaction was concentrated to dryness. The residuewas taken up in EtOAc (50 mL). The organic layer was washed with 2×50 mLwater then 1×50 mL saturated brine. The organic layer was separated,dried (MgSO₄), filtered, and concentrated. The residue was purified byprep-TLC to give((3aR,4R,6R,6aR)-6-(2-chloro-4-(((R)-1-(2,4-difluorophenyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(200 mg, 0.42 mmol, 75% yield) as colorless liquid. LCMS ESI (+) m/z 481(M+H).

Step B: To solution of((3aR,4R,6R,6aR)-6-(2-chloro-4-(((R)-1-(2,4-difluorophenyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(165 mg, 0.34 mmol) in pyridine (2 mL, 0.34 mmol) at 0° C. was addedmethanesulfonyl chloride (47 mg, 0.41 mmol) under N₂. The mixture wasstirred for 2 h at 0° C. The reaction mixture was diluted with EtOAc (30mL) and the organic layer was washed with 2×30 mL water then 1×30 mLsaturated brine. The organic layer was separated, dried (MgSO₄),filtered, and concentrated. The residue was purified by prep-TLC to give((3aR,4R,6R,6aR)-6-(2-chloro-4-(((R)-1-(2,4-difluorophenyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylmethanesulfonate (180 mg, 0.32 mmol, 94% yield) as a white solid.

Step C: To a mixture of EtONa (65.74 mg, 0.9700 mmol) in DMF (5 mL) wasadded [amino(diethoxyphosphorylmethylsulfanyl)methylene]ammonium;4-methylbenzenesulfonate (192.46 mg, 0.4800 mmol) under N₂. The mixturewas stirred for 1.5 h at room temperature under N₂. A solution of((3aR,4R,6R,6aR)-6-(2-chloro-4-(((R)-1-(2,4-difluorophenyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylmethanesulfonate (180 mg, 0.32 mmol) in DMF (lmL) was added. The mixturewas stirred for 1.5 h at room temperature under N₂. The reaction mixturewas diluted with EtOAc (60 mL) and washed with 2×60 mL water then 1×60mL saturated brine. The organic layer was separated, dried (MgSO₄),filtered, and concentrated. The residue was purified by prep-TLC to givediethyl(((((3aS,4S,6R,6aR)-6-(2-chloro-4-(((R)-1-(2,4-difluorophenyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)thio)methyl)phosphonate(110 mg, 0.17 mmol, 53% yield) as colorless liquid. LCMS ESI (+) m/z 647(M+H).

Step D: A mixture of diethyl(((((3aS,4S,6R,6aR)-6-(2-chloro-4-(((R)-1-(2,4-difluorophenyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)thio)methyl)phosphonate(110 mg, 0.17 mmol) and Oxone (314 mg, 0.51 mmol) in water (2 mL) andacetonitrile (2 mL) was stirred at room temperature for 3.5 h. Thereaction mixture was diluted with EtOAc (30 mL). The organic layer waswashed with 2×30 mL water, separated, dried (MgSO₄), filtered, andconcentrated. The residue was purified by prep-TLC to give diethyl(((((3aS,4S,6R,6aR)-6-(2-chloro-4-(((R)-1-(2,4-difluorophenyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfonyl)methyl)phosphonate(35 mg, 0.052 mmol, 30% yield) as a white solid. LCMS ESI (+) m/z 679(M+H).

Step E: A mixture of diethyl(((((3aS,4S,6R,6aR)-6-(2-chloro-4-(((R)-1-(2,4-difluorophenyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfonyl)methyl)phosphonate(35 mg, 0.05 mmol), TMSBr (118 mg, 0.77 mmol) and 2,6-lutidine (77 mg,0.72 mmol) in dichloromethane (2 mL) was stirred at room temperature for16 h. The reaction mixture was concentrated to dryness and crude(((((3aS,4S,6R,6aR)-6-(2-chloro-4-(((R)-1-(2,4-difluorophenyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfonyl)methyl)phosphonicacid (110 mg) was obtained as a white solid. LCMS ESI (−) m/z 621 (M−H).

Step F: A mixture of(((((3aS,4S,6R,6aR)-6-(2-chloro-4-(((R)-1-(2,4-difluorophenyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfonyl)methyl)phosphonicacid (crude from Step E) in 80% aqueous formic acid (2 mL, 0.18 mmol)was stirred at room temperature for 2 h. The reaction mixture wasconcentrated to dryness and the residue was purified by prep-HPLC togive(((((2S,3S,4R,5R)-5-(2-chloro-4-(((R)-1-(2,4-difluorophenyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonicacid (15 mg, 0.026 mmol, 15% yield) as a white solid. LCMS ESI (−) m/z581 (M−H).

Example 16: Synthesis of(((((2S,3S,4R,5R)-5-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonicacid (Compound 155)

Step A: Preparation of((3aR,4R,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol:To a mixture of((3aR,4R,6R,6aR)-6-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(0.81 g, 2.25 mmol) and DIEA (0.6 mL, 3.38 mmol) in s-butanol (4 mL) wasadded cyclopentanamine (0.38 g, 4.51 mmol) at ambient temperature. Themixture was stirred at 100° C. in a pressure tube for 4 hours. Solventwas removed under reduced pressure. The residue obtained was purified byflash chromatography on silica gel (3:1 DCM/ethyl acetate) to give((3aR,4R,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(0.40 g, 43%) as solid. LCMS ESI (−) m/z 407 (M−H).

Step B: Preparation of((3aR,4R,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylmethanesulfonate: To a solution of((3aR,4R,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(0.07 g, 0.17 mmol) in pyridine (2 mL) was added methanesulfonylchloride (0.01 mL, 0.19 mmol) at 0° C. The reaction mixture was stirredat 0° C. for 2 hours. Saturated sodium bicarbonate solution (10 mL) andMTBE (10 mL) were added. The organic layer was separated, washed withbrine, dried (sodium sulfate), filtered and concentrated under reducedpressure to give((3aR,4R,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylmethanesulfonate (0.083 g, 100%) as a solid. LCMS ESI (+) m/z 487 (M+H).

Step C: Preparation ofS-(((3aS,4S,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)ethanethioate: To a solution of((3aR,4R,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(0.08 g, 0.17 mmol) in DMF (3 mL) was added tetrabutylammonium bromide(0.01 g, 0.02 mmol) and potassium ethanethioate (0.03 g, 0.26 mmol) atambient temperature. The reaction mixture was stirred at ambienttemperature for 24 hours. Water (10 mL) and MTBE (15 mL) were added. Theorganic layer was separated, washed with brine, dried (sodium sulfate),filtered and concentrated under reduced pressure. The residue obtainedwas purified by flash chromatography on silica gel (1:1 hexane/ethylacetate) to giveS-(((3aS,4S,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)ethanethioate (0.07 g, 88%) as a solid. LCMS ESI (+) m/z 467 (M+H).

Step D: Preparation of((3aS,4S,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanethiol:To a solution ofS-(((3aS,4S,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)ethanethioate (0.07 g, 0.15 mol) was added 7N ammonia in methanol (2.21mL, 15.5 mmol) at ambient temperature. The reaction mixture was stirredat ambient temperature for 4 hours. Solvent was removed under reducedpressure to give [(3aR,4R,6S,6aS)-4-[2-chloro-6-[[(1S)-1-(4-fluorophenyl)ethyl]amino]purin-9-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanethiol(0.064 g, 100%) as a solid. LCMS ESI (+) m/z 425 (M+H).

Step E: Preparation of diisopropyl(((((3aS,4S,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)thio)methyl)phosphonate:Sodium hydride (60%) (0.01 g, 0.33 mmol) was added to a mixture of[(3aR,4R,6S,6aS)-4-[2-chloro-6-[[(1S)-1-(4-fluorophenyl)ethyl]amino]purin-9-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanethiol(0.06 g, 0.15 mmol) and diisopropyl (bromomethyl)phosphonate (0.08 g,0.30 mmol) at 0° C. The reaction mixture was stirred at this temperaturefor 30 minutes. Saturated ammonium chloride solution and MTBE (15 mL)were added. The organic layer was separated, washed with brine, dried(sodium sulfate), filtered and concentrated under reduced pressure. Theresidue obtained was purified by flash chromatography on silica gel(ethyl acetate) to give diisopropyl(((((3aS,4S,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)thio)methyl)phosphonate(0.053 g, 58%) as an oil. LCMS ESI (−) m/z 601 (M−H).

Step F: Preparation of diisopropyl(((((3aS,4S,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfonyl)methyl)phosphonate:To a solution of diisopropyl(((((3aS,4S,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)thio)methyl)phosphonate(0.05 g, 0.09 mmol) in acetonitrile (3 mL) and water (3 mL) was addedOxone (0.16 g, 0.53 mmol) at ambient temperature. The mixture wasstirred at ambient temperature for 5 hours. Ethyl acetate (10 mL) andwater (10 mL) were added. The organic layer was separated, washed withbrine, dried (sodium sulfate), filtered and concentrated under reducedpressure. The residue obtained was purified chromatography on silica gel(ethyl acetate) to give diisopropyl(((((3aS,4S,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfonyl)methyl)phosphonate(0.013 g, 23%) as a solid. LCMS ESI (−) m/z 633 (M−H).

Step G: Preparation of(((((2S,3S,4R,5R)-5-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonicacid: To a solution of 7 diisopropyl(((((3aS,4S,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfonyl)methyl)phosphonate(0.01 g, 0.02 mmol) in dichloromethane (2 mL) was added 2,6-Lutidine(0.02 mL, 0.20 mmol) and bromotrimethylsilane (0.03 mL, 0.20 mmol) atambient temperature. The reaction mixture was stirred at thistemperature for 18 hours. The reaction mixture was concentrated underreduced pressure. The residue was co-evaporated with methanol threetimes to give a light yellow solid. 80% formic acid in water (2 mL) wasadded. The mixture was stirred at ambient temperature for 6 hours. Themixture was concentrated at reduced pressure and co-evaporated withmethanol three times to give a thick oil. It was purified by preparativeHPLC (10%-80% ACN/H₂O, 0.1% TFA) to give(((((2S,3S,4R,5R)-5-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonicacid (0.009 g, 70%) as a TFA salt. LCMS ESI (−) m/z 509 (M−H).

Example 17: Synthesis of((((((2R,3S,4R,5R)-5-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)methyl)phosphonicacid (Compound 229)

Step A: Preparation of((((((3aR,4R,6R,6aR)-6-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(hydroxy)phosphoryl)oxy)methyl)phosphonicacid: To a solution of[(3aR,4R,6R,6aR)-4-(2,4-dichloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol(0.08 g, 0.21 mmol) and 2,6-lutidine (0.074 mL, 0.64 mmol) intetrahydrofuran (5 mL) was added a solution ofP,P′-methylenebis-phosphonic dichloride (0.08 g, 0.32 mmol) in THF (0.2mL) at 0° C. The reaction mixture was stirred at 0° C. for 5 hours.Saturated sodium bicarbonate solution (10 mL) and MTBE (30 mL) wereadded. The aqueous layer was separated and concentrated under reducedpressure. The residue obtained was purified by reverse phase columnchromatography with CH₃CN/water (0% to 80%) to give[[(3aR,4R,6R,6aR)-4-(2,4-dichloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxy-hydroxy-phosphoryl]methylphosphonicacid (0.046 g, 41%) as a solid. LCMS ESI (+) m/z 518 (M+H).

Step B: Preparation of[[(3aR,4R,6R,6aR)-4-(2,4-dichloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxy-hydroxy-phosphoryl]methylphosphonicacid: A suspension of[[(3aR,4R,6R,6aR)-4-(2,4-dichloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxy-hydroxy-phosphoryl]methylphosphonicacid (0.046 g, 0.08 mmol), cyclopentanamine (0.01 g, 0.16 mmol) andtriethylamine (0.02 mL, 0.12 mmol) in s-Butanol (2 mL) was stirred at100° C. for 4 hours. After cooling to ambient temperature, the solventwas removed under reduced pressure. The residue obtained was purified bypreparative reverse phase HPLC (10%-95% ACN/H₂O, 0.1% TFA) to give[[(3aR,4R,6R,6aR)-4-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxy-hydroxy-phosphoryl]methylphosphonicacid (0.025 g, 54%) as a solid. LCMS ESI (+) m/z 567 (M+H).

Step C: Preparation of((((((2R,3S,4R,5R)-5-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)methyl)phosphonicacid: A solution of[[(3aR,4R,6R,6aR)-4-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxy-hydroxy-phosphoryl]methylphosphonicacid (0.03 g, 0.04 mmol) in 80% formic acid (2 mL) was stirred atambient temperature for 2 hours. Solvent was removed under reducedpressure. The residue was purified by preparative reverse phase HPLC(10%-95% ACN/H₂O, 0.1% TFA) to give[[(2R,3S,4R,5R)-5-[2-chloro-4-(cyclopentylamino)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxy-hydroxy-phosphoryl]methylphosphonicacid; 2,2,2-trifluoroacetic acid (0.013 g, 46%) as a solid. LCMS ESI (+)m/z 527 (M+H).

Example 18: Synthesis of((((2R,3S,4R,5R)-5-(6-chloro-4-(cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonicacid (Compound 240)

Step A: Preparation of(2R,3R,4R,5R)-2-(acetoxymethyl)-5-(4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-diyldiacetate: 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (2.5 g, 13.2 mmol)and ammonium sulfate (19.8 mg, 0.15 mmol) were dissolved inhexamethyldisilane (18 mL). The mixture was warmed to reflux and stirredfor 3 hrs. The mixture was then concentrated under reduced pressure. Theresidue was then taken up in acetic anhydride (36 mL), and(2S,3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetate(5.1 g, 15.9 mmol) was added. This mixture was cooled to 0° C. andTMSOTf (3.2 g, 14.6 mmol) was added dropwise. The mixture was warmed toambient temperature and stirred at ambient temperature overnight. Themixture was then concentrated under reduced pressure. The residue wassuspended in ethyl acetate, washed with saturated sodium bicarbonatesolution and brine. The organics were dried with sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel to give[(2R,3R,4R,5R)-3,4-diacetoxy-5-(4,6-dichloropyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-2-yl]methylacetate (3.3 g, 56%) as a solid.

Step B: Preparation of(2R,3R,4S,5R)-2-(6-chloro-4-(cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol:To a solution of[(2R,3R,4R,5R)-3,4-diacetoxy-5-(4,6-dichloropyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-2-yl]methylacetate (3.3 g, 7.4 mmol) in methanol (16 mL) was added cyclopentanamine(0.66 g, 7.8 mmol) and triethylamine (0.78 g, 7.8 mmol) at 0° C. Themixture was warmed to ambient temperature and stirred at ambienttemperature for 4 hours. 7 N ammonium in MeOH (12 mL) was added and thereaction mixture was stirred at ambient temperature for 24 hours. Thereaction mixture was concentrated under reduced pressure to give(2R,3R,4S,5R)-2-[6-chloro-4-(cyclopentylamino)pyrazolo[3,4-d]pyrimidin-1-yl]-5-(hydroxymethyl)tetrahydrofuran-3,4-diol(3.0 g, 88%) which was used directly in the next step withoutpurification.

Step C: Preparation of((3aR,4R,6R,6aR)-6-(6-chloro-4-(cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol:A mixture of(2R,3R,4S,5R)-2-[6-chloro-4-(cyclopentylamino)pyrazolo[3,4-d]pyrimidin-1-yl]-5-(hydroxymethyl)tetrahydrofuran-3,4-diol(3.01 g, 8.1 mmol), 2,2-dimethoxy propane (12.7 g, 122.0 mmol), TsOH(2.01 g, 10.6 mmol) in acetone (80 mL) was stirred at ambienttemperature for 16 hours. Sodium bicarbonate (0.4 g) and water (200 mL)were added. The mixture was stirred for 1 h and then extracted withethyl acetate. The organics were separated and dried (MgSO₄), filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel to give[(2R,3R,4R,5R)-5-[6-chloro-4-(cyclopentylamino)pyrazolo[3,4-d]pyrimidin-1-yl]-3,4-diethoxy-tetrahydrofuran-2-yl]methanol(2.3 g, 66%) as a solid.

Step D: Preparation of diethyl((((3aR,4R,6R,6aR)-6-(6-chloro-4-(cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate:A mixture of[(3aR,4R,6R,6aR)-4-[6-chloro-4-(cyclopentylamino)pyrazolo[3,4-d]pyrimidin-1-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol(200.5 mg, 0.49 mmol),1-(diethoxyphosphorylmethylsulfonyl)-4-methyl-benzene (299.7 mg, 0.98mmol) and magnesium 2-methylpropan-2-olate (334.6 mg, 1.96 mmol) in DMSO(5 mL) was stirred at 80° C. for 4 hours. After cooling to ambienttemperature, saturated ammonium chloride solution (50 mL) and MTBE (30mL) were added. The organic layer was separated, washed with brine,dried (sodium sulfate), filtered and concentrated under reducedpressure. The residue was purified by flash chromatography on silica gel10:1 ethyl acetate/methanol to give1-[(3aR,4R,6R,6aR)-6-(diethoxyphosphorylmethoxymethyl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-6-chloro-N-cyclopentyl-pyrazzol[3,4-d]pyrimidin-4-amine(186 mg, 68%) as a solid.

Step E: Preparation of((((3aR,4R,6R,6aR)-6-(6-chloro-4-(cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonicacid: To a solution of1-[(3aR,4R,6R,6aR)-6-(diethoxyphosphorylmethoxymethyl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-6-chloro-N-cyclopentyl-pyrazolo[3,4-d]pyrimidin-4-amine(90.0 mg, 0.16 mmol) and 2,6-lutidine (344.4 mg, 3.2 mmol) indichloromethane (5 mL) was added bromotrimethylsilane (492.1 mg, 3.2mmol). The mixture was stirred at ambient temperature overnight. Themixture was concentrated under reduced pressure. The residue wasco-evaporated with ACN twice to give[(3aR,4R,6R,6aR)-4-[6-chloro-4-(cyclopentylamino)pyrazolo[3,4-d]pyrimidin-1-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxymethylphosphonicacid which was used directly in the next step.

Step F: Preparation of((((2R,3S,4R,5R)-5-(6-chloro-4-(cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonicacid: A solution of[(3aR,4R,6R,6aR)-4-[6-chloro-4-(cyclopentylamino)pyrazolo[3,4-d]pyrimidin-1-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxymethylphosphonicacid (90.0 mg, 0.18 mmol) in 80% HCOOH (3 mL) was stirred at ambienttemperature for 2 hours. The mixture was concentrated under reducedpressure and purified by preparative reverse phase HPLC (10%-95%ACN/H₂O, 0.1% TFA) to give[(2R,3S,4R,5R)-5-[6-chloro-4-(cyclopentylamino)pyrazolo[3,4-d]pyrimidin-1-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonicacid (46 mg, 45%) as a solid. LCMS ESI (+) m/z 462 (M−H).

Example 19: Synthesis of(((((2S,3S,4R,5R)-5-(6-cyano-4-(cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonicacid (Compound 296)

Step A: Preparation of4-(cyclopentylamino)-1-((3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile:A solution of [(3aR,4R,6R,6aR)-4-[6-chloro-4-(cyclopentylamino)pyrazolo[3,4-d]pyrimidin-1-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol(100.0 mg, 0.24 mmol), zinc cyanide (143.2 mg, 1.22 mmol) and Pd(PPh₃)₄(281.9 mg, 0.24 mmol) in 1-Methyl-2-pyrrolidone (5 mL) in a sealed tubewas stirred at 100° C. under nitrogen for 6 hours. After cooling toambient temperature, the mixture was diluted with ethyl acetate,filtered through celite and washed with ethyl acetate. The filtrate waswashed with brine, dried (Na₂SO₄), filtered and concentrated underreduced pressure. The residue was purified by preparative TLC to give1-[(3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-4-(cyclopentylamino)pyrazolo[3,4-d]pyrimidine-6-carbonitrile(90 mg, 92%) as a solid.

Step B: Preparation of((3aR,4R,6R,6aR)-6-(6-cyano-4-(cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylmethanesulfonate: To a solution of1-[(3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-4-(cyclopentylamino)pyrazolo[3,4-d]pyrimidine-6-carbonitrile(87.9 mg, 0.22 mmol) in pyridine (5 mL) was added methanesulfonylchloride (37.7 mg, 0.33 mmol) at 0° C., and the resulting mixture wasstirred at this temperature for 2 hours. Solvent was removed underreduced pressure. The residue was partitioned between water and ethylacetate. The organic layer was separated, dried over Na₂SO₄, filtered,concentrated under reduced pressure and purified by preparative TLC togive[(3aR,4R,6R,6aR)-4-[6-cyano-4-(cyclopentylamino)pyrazolo[3,4-d]pyrimidin-1-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methylmethanesulfonate (90 mg, 85%) as a solid.

Step C: Preparation of diethyl(((((3aS,4S,6R,6aR)-6-(6-cyano-4-(cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)thio)methyl)phosphonate:To a solution of NaOEt (38.3 mg, 0.56 mmol) in DMF (4 mL) was added[[amino(diethoxyphosphorylmethylsulfanyl)methylene]ammonium;4-methylbenzenesulfonate (149.9 mg, 0.38 mmol) under nitrogen at ambienttemperature.[(3aR,4R,6R,6aR)-4-[6-cyano-4-(cyclopentylamino)pyrazolo[3,4-d]pyrimidin-1-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methylmethanesulfonate (90.0 mg, 0.19 mmol) in DMF (1 mL) was added after 30minutes. The mixture was stirred at 40° C. for 16 hours. After coolingto ambient temperature, the mixture was dilute with ethyl acetate andwater. The organic layer was separated, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified bypreparative TLC to give 1-[(3aR,4R,6S,6aS)-6-(diethoxyphosphorylmethylsulfanylmethyl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-4-(cyclopentylamino)pyrazolo[3,4-d]pyrimidine-6-carbonitrile(70 mg, 65%) as a solid.

Step D: Preparation of((((3aR,4R,6R,6aR)-6-(6-chloro-4-(cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonicacid: To a solution of1-[(3aR,4R,6S,6aS)-6-(diethoxyphosphorylmethylsulfanylmethyl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-4-(cyclopentylamino)pyrazolo[3,4-d]pyrimidine-6-carbonitrile(70.0 mg, 0.12 mmol) in acetonitrile (3 mL) and water (3 mL) was addedOxone (227.9 mg, 0.37 mmol). The mixture was stirred at ambienttemperature for 6 hours and partitioned between water and ethyl acetate.The organic layer was separated, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified bypreparative TLC to give 1-[(3aR,4R,6S,6aS)-6-(diethoxyphosphorylmethylsulfonylmethyl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-4-(cyclopentylamino)pyrazolo[3,4-d]pyrimidine-6-carbonitrile(22 mg, 29%) as a solid.

Step E: Preparation of(((((3aS,4S,6R,6aR)-6-(6-cyano-4-(cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfonyl)methyl)phosphonicacid: To a solution of1-[(3aR,4R,6S,6aS)-6-(diethoxyphosphorylmethylsulfonylmethyl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-4-(cyclopentylamino)pyrazolo[3,4-d]pyrimidine-6-carbonitrile(22.0 mg, 0.04 mmol) and 2,6-lutidine (78.8 mg, 0.74 mmol) indichloromethane (5 mL) was added bromotrimethylsilane (112.5 mg, 0.74mmol). The mixture was stirred at ambient temperature overnight and thenconcentrated under reduced pressure. The residue was co-evaporated withACN twice to give[(3aR,4R,6S,6aS)-4-[6-cyano-4-(cyclopentylamino)pyrazolo[3,4-d]pyrimidin-1-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methylsulfonylmethylphosphonicacid which was used directly in the next step.

Step F: Preparation of(((((2S,3S,4R,5R)-5-(6-cyano-4-(cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonicacid: A solution of[(3aR,4R,6S,6aS)-4-[6-cyano-4-(cyclopentylamino)pyrazolo[3,4-d]pyrimidin-1-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methylsulfonylmethylphosphonicacid (35.0 mg, 0.03 mmol) in 80% HCOOH (3 mL) was stirred at ambienttemperature for 2 hours. The mixture was concentrated under reducedpressure and purified by preparative reverse phase HPLC (10%-95%ACN/H₂O, 0.1% TFA) to give[(2S,3S,4R,5R)-5-[6-cyano-4-(cyclopentylamino)pyrazolo[3,4-d]pyrimidin-1-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methylsulfonylmethylphosphonicacid (11.5 mg, 88%) as a solid. LCMS ESI (+) m/z 501 (M−H).

Example 20: Synthesis of ((((2R,3S,4R,5S)-5-(2-chloro-4-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonicacid (Compound 285)

Step A: Preparation of 7-bromo-2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine:To a solution of, 2,4-dichloro-5H-Pyrrolo[3,2-d]pyrimidine (1.88 g, 10mmol) in DMF (10 mL) was added N-bromosuccinimide (1.96 g, 11 mmol) atambient temperature. The mixture was stirred at ambient temperature for1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate solution(20 mL) were added. The organic layer was separated, washed with brine,dried (sodium sulfate), filtered and concentrated under reducedpressure. The residue was purified by flash chromatography on silica gel(1:1 hexane/ethyl acetate) to give7-bromo-2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (2.3 g, 86%) as asolid.

Step B: Preparation of5-(benzenesulfonyl)-7-bromo-2,4-dichloro-pyrrolo[3,2-d]pyrimidine: To asolution of 7-bromo-2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (1.0 g,3.75 mmol), DIEA (1.0 mL, 5.62 mmol) and 4-(dimethylamino)pyridine (0.05g, 0.37 mmol) in dichloromethane (30 mL) was added benzenesulfonylchloride (0.57 mL, 4.5 mmol) at 0° C. The mixture was stirred at 0° C.for 1 hour. Saturated sodium bicarbonate solution (20 mL) was added. Theorganic layer was separated, washed with brine, dried (sodium sulfate),filtered and concentrated under reduced pressure. The residue obtainedwas purified by flash chromatography on silica gel (1:1 hexane/DCM) togive 5-(benzenesulfonyl)-7-bromo-2,4-dichloro-pyrrolo[3,2-d]pyrimidine(1.15 g, 75%) as a solid.

Step C: Preparation of(3aR,4S,6R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-4-(2,4-dichloro-5-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol:To a solution of(3aR,6R,6aR)-6-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-4-one (1.28 g, 4.24 mmol) and5-(benzenesulfonyl)-7-bromo-2,4-dichloro-pyrrolo[3,2-d]pyrimidine (1.15g, 2.83 mmol) in tetrahydrofuran (20 mL) was added n-butyllithiumsolution (2.5M in hexane, 1.36 mL, 3.39 mmol) dropwise at −78° C. (30minutes). After the addition, the mixture was stirred at −78° C. for 2hours and then quenched with acetic acid (0.26 mL, 4.52 mmol). Theresulting mixture was warmed to ambient temperature, diluted with ethylacetate, and washed with water. The organic layer was separated, washedwith brine, dried (sodium sulfate), filtered and concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel (5:1 hexane/ethyl acetate) to give(3aR,4S,6R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-4-(2,4-dichloro-5-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol(1.12 g, 31%) as a solid.

Step D: Preparation of(3R,4S,5R)-2-[5-(benzenesulfonyl)-2,4-dichloro-pyrrolo[3,2-d]pyrimidin-7-yl]-5-(hydroxymethyl)tetrahydrofuran-3,4-diol:To a solution of(3aR,6R,6aR)-4-[5-(benzenesulfonyl)-2,4-dichloro-pyrrolo[3,2-d]pyrimidin-7-yl]-6-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-4-ol (0.67 g, 1.07 mmol) in dichloromethane(10 mL) was added triethylsilane (0.68 mL, 4.26 mmol), then borontrifluoride diethyl etherate (0.39 mL, 3.2 mmol) at ambient temperature.The reaction mixture was stirred at ambient temperature for 18 hours.The reaction mixture was cooled with ice bath and slowly quenched withsaturated sodium bicarbonate solution. The organic layer was separated,washed with brine, dried (sodium sulfate), filtered and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel (ethyl acetate) to give(3R,4S,5R)-2-[5-(benzenesulfonyl)-2,4-dichloro-pyrrolo[3,2-d]pyrimidin-7-yl]-5-(hydroxymethyl)tetrahydrofuran-3,4-diol(1.0 g, 91%) as a solid.

Step E: Preparation of[(3aS,6R,6aR)-4-[5-(benzenesulfonyl)-2,4-dichloro-pyrrolo[3,2-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol:To a solution of(3R,4S,5R)-2-[5-(benzenesulfonyl)-2,4-dichloro-pyrrolo[3,2-d]pyrimidin-7-yl]-5-(hydroxymethyl)tetrahydrofuran-3,4-diol(1.0 g, 2.17 mmol) and 2,2-dimethoxy propane (3.19 mL, 26.1 mmol) inacetone (10 mL) was added 4-methylbenzenesulfonic acid (0.49 g, 2.82mmol) at ambient temperature. The reaction mixture was stirred atambient temperature for 2 hours. Solvent was removed under reducepressure. Water (20 mL) and ethyl acetate (20 mL) were added. Theorganic layer was separated, washed with brine, dried (sodium sulfate),filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel 1:1 hexane/ethyl acetateto give[(3aS,6R,6aR)-4-[5-(benzenesulfonyl)-2,4-dichloro-pyrrolo[3,2-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol(0.42 g, 38%) as a solid.

Step F: Preparation of[(3aS,4S,6R,6aR)-4-[4-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-5-(benzenesulfonyl)-2-chloro-pyrrolo[3,2-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol:A solution of[(3aS,6R,6aR)-4-[5-(benzenesulfonyl)-2,4-dichloro-pyrrolo[3,2-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol(0.42 g, 0.84 mmol), 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole(0.14 g, 1.26 mmol) and triethylamine (0.23 mL, 1.68 mmol) in s-Butanol(5 mL) was stirred at 80° C. for 1 hour. After cooling to ambienttemperature, s-butanol was removed under reduced pressure. Ethyl acetate(20 ml) and water (10 mL) were added. The organic layer was separated,washed with brine, dried (sodium sulfate), filtered and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel (1:1 hexane/ethyl acetate) to give[(3aS,4S,6R,6aR)-4-[4-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-5-(benzenesulfonyl)-2-chloro-pyrrolo[3,2-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol(0.148 g, 30%) as a solid.

Step G: Preparation of7-[(3aS,4S,6R,6aR)-6-(diethoxyphosphorylmethoxymethyl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-4-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-5-(benzenesulfonyl)-2-chloro-pyrrolo[3,2-d]pyrimidine:A mixture of[(3aS,4S,6R,6aR)-4-[4-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-5-(benzenesulfonyl)-2-chloro-pyrrolo[3,2-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol(0.12 g, 0.22 mmol), P-[[[(4-methylphenyl)sulfonyl]oxy]methyl]phosphonicacid diethyl ester (0.14 g, 0.43 mmol) and magnesium2-methylpropan-2-olate (0.15 g, 0.86 mmol) in dimethyl sulfoxide (3 mL)was stirred at 80° C. (bath) for 4 hours. After cooling to ambienttemperature, saturated ammonium chloride solution (10 mL) and 1:1MTBE/ethyl acetate (20 mL) were added. The organic layer was separated,washed with brine, dried (sodium sulfate), filtered and concentratedunder reduced pressure. The residue was purified by reverse phase column(Biotage Isolera One unit, Biotage@SNAP Ultra C18 60 g column, 30-100%CH₃CN/water, 10 CV) to give7-[(3aS,4S,6R,6aR)-6-(diethoxyphosphorylmethoxymethyl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-4-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-5-(benzenesulfonyl)-2-chloro-pyrrolo[3,2-d]pyrimidine(0.044 g, 28%) as an oil.

Step H: Preparation of [(2R,3S,4R,5S)-5-[4-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-2-chloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonicacid: To a solution of7-[(3aS,4S,6R,6aR)-6-(diethoxyphosphorylmethoxymethyl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-4-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-5-(benzenesulfonyl)-2-chloro-pyrrolo[3,2-d]pyrimidine(0.040 g, 0.06 mmol) in dichloromethane (2 mL) was added 2,6-lutidine(0.04 mL, 0.30 mmol) and bromotrimethyl silane (0.04 mL, 0.30 mmol) atambient temperature. The reaction mixture was stirred at thistemperature for 18 hours. The reaction mixture was concentrated underreduced pressure. The residue was co-evaporated with methanol threetimes to give a light yellow solid. The solid was dissolved in 1:1THF/water (6 mL) and sodium hydroxide (0.07 g, 1.82 mmol) was added. Themixture was stirred at ambient temperature for 1 hour and at 55° C.(bath) for 3 hours. THF and water were removed under reduced pressure.80% Formic acid in water (3 mL) was added. The resulting mixture wasstirred at ambient temperature for 3 hours. Formic acid was removedunder reduced pressure. The residue was co-evaporated with methanolthree times to give a light yellow solid, which was directly purified bypreparative reverse phase HPLC (5%-95% ACN/H₂O, 0.1% TFA) to give[(2R,3S,4R,5S)-5-[4-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-2-chloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxymethylphosphonicacid (0.007 g, 19%) as a solid. LCMS ESI (+) m/z 489 (M+H).

Example 21: Synthesis of((((2R,3S,4R,5R)-5-(4-(cyclopentylamino)-2-((1-hydroxycyclopropyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonicacid (Compound 276)

Step A: Isopentyl nitrite (5.2 g, 44.39 mmol) was added to a stirredmixture of 7-((3aR,4R,6R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-amine(8.6 g, 14.85 mmol), CuI (3. g, 15.75 mmol), iodine (4.0 g, 15.76 mmol)and diiodomethane (40 g, 149.3 mmol) in tetrahydrofuran (100 mL) at roomtemperature. The mixture was then stirred at 80° C. for 45 minutes. Thecooled reaction mixture was poured into an aqueous solution of sodiumsulphite and extracted with EtOAc. The combined extracts were washedwith brine, dried over anhydrous Na₂SO₄ and the solvent was evaporated.The residue was purified by column chromatography (EtOAc:petroleum ether1:8) to give7-((3aR,4R,6R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-4-chloro-2-iodo-7H-pyrrolo[2,3-d]pyrimidine(4.0 g, 39%).

Step B: A solution of7-((3aR,4R,6R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-4-chloro-2-iodo-7H-pyrrolo[2,3-d]pyrimidine(1.2 g, 1.7 mmol) and cyclopentanamine (0.5 g, 5.9 mmol) in ethanol (5mL) was stirred in a sealed tube at 80° C. overnight. The reactionmixture was then concentrated and purified by column chromatography(EtOAc:hexanes 1:8) to give the product7-((3aR,4R,6R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-N-cyclopentyl-2-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(1.1 g, 86%).

Step C: To a solution of7-((3aR,4R,6R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-N-cyclopentyl-2-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(1.3 g, 1.76 mmol) in THF (20 mL) was added a solution oftetrabutylammonium fluoride, 1.0M in THF (1.91 mL, 1.91 mmol) 0° C. Thereaction mixture was stirred at 25° C. for 3 h. The mixture was dilutedwith EtOAc, washed with brine, then dried (Na₂SO₄) and filtered beforeconcentration to dryness. The crude residue was purified by columnchromatography eluting with 30% EtOAc/hexane to give((3aR,4R,6R,6aR)-6-(4-(cyclopentylamino)-2-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(700 mg, 80%) as an off-white solid. LCMS ESI (+) m/z 501, M+H.

Step D:((3aR,4R,6R,6aR)-6-(4-(cyclopentylamino)-2-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(85 mg, 0.17 mmol), ditert-butoxymagnesium (65.7 mg, 0.39 mmol) and(diethoxyphosphoryl)methyl 4-methylbenzenesulfonate (130.5 mg, 0.4 mmol)and DMSO (0.6 mL) were successively charged to a 20 mL scintillationvial. The vial was placed in an 80° C. oil bath and aged for 6 hours atthis temperature. The cooled reaction mixture was partitioned with EtOAcand saturated aqueous NH₄Cl. The aqueous separation was extracted withEtOAc (2×). The combined organic extracts were washed with brine (2×)then dried with Na₂SO₄, filtered and concentrated to an orange oil. Theoil was purified by column chromatography, 10 g SiO₂, 5 to 50% (3:1EtOAc:EtOH (v/v))/hexanes to give diethyl((((3aR,4R,6R,6aR)-6-(4-(cyclopentylamino)-2-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonateas a tan colored oil. LCMS ESI (+) m/z 651, M+H.

Step E: Pd(PPh₃)₂Cl₂ (8.4 mg, 0.012 mmol) and CuI (4.6 mg, 0.024 mmol)were charged to a vial. A solution of diethyl((((3aR,4R,6R,6aR)-6-(4-(cyclopentylamino)-2-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(40 mg, 0.06 mmol) in 1,4-dioxane (1 mL) was added to the vial, followedby Et₃N (15.3 mg, 0.15 mmol). The yellowed orange solution was spargedwith argon for 3 minutes, then treated with 1-ethynylcyclopropanol (120mg, 1.46 mmol), and within a minute had turned a black color. Themixture was stirred at ambient temperature for 90 minutes. The reactionmixture was diluted with ethyl acetate, then filtered over celite. Thefiltrate was concentrated under reduced pressure, then the residue waspurified by column chromatography, 80% EtOAc/hexane, to give diethyl((((3aR,4R,6R,6aR)-6-(4-(cyclopentylamino)-2-((1-hydroxycyclopropyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(24 mg, 64% yield).

Step F: To a solution of diethyl((((3aR,4R,6R,6aR)-6-(4-(cyclopentylamino)-2-((1-hydroxycyclopropyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(24 mg, 0.04 mmol) and 2,6-lutidine (50 mg, 0.47 mmol) in DCM (5 mL) wasadded bromotrimethylsilane (70 mg, 0.46 mmol). The mixture was stirredat ambient temperature overnight, then was concentrated under reducedpressure. The residue was coevaporated with CH₃CN (2×) to give((((3aR,4R,6R,6aR)-6-(4-(cyclopentylamino)-2-((1-hydroxycyclopropyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonicacid (28 mg) as a crude product, which was carried forward withoutfurther purification.

Step G: A solution of((((3aR,4R,6R,6aR)-6-(4-(cyclopentylamino)-2-((1-hydroxycyclopropyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonicacid (28 mg, 0.05 mmol) in 80% HCOOH aqueous solution (3 mL) was stirredat ambient temperature for 2 h. The mixture was concentrated underreduced pressure at 30° C., then purified by reverse phase HPLC, 20% to80% MeCN/H₂O with 0.1% TFA, 15 min gradient, to afford((((2R,3S,4R,5R)-5-(4-(cyclopentylamino)-2-((1-hydroxycyclopropyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonicacid (5.1 mg, 20% yield) as a white solid. LCMS ESI (+) m/z 508.5, M+H.

Example 22: Synthesis of((((2R,3S,4R,5R)-5-(4-(cyclopentylamino)-2-(2-hydroxyethoxy)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonicacid (Compound 257)

Step A: Sodium hydride (40 mg, 1.67 mmol) was weighed into a vial, thenethylene glycol (0.5 mL, 8.97 mmol) was slowly added, which effervescedand was very exothermic. After the gas evolution had ceased, and themixture cooled,((((3aR,4R,6R,6aR)-6-(2-chloro-4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonicacid (20 mg, 0.04 mmol) was added in a single portion. The vial wascapped and warmed to 110° C. and stirred for 90 minutes, then was cooledto ambient temperature; the solution was very viscous. The solution wasdiluted with methanol (0.5 mL), and then treated with 6N aqueous HCl(1.0 mL) and stirred overnight. The solution was purified by HPLC, 5 to90% MeCN/H₂O (with 0.1% TFA) over a 10 minute gradient to give a clearfilm,((((3aR,4R,6R,6aR)-6-(4-(cyclopentylamino)-2-(2-hydroxyethoxy)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonicacid (18.3 mg, 94% yield). LCMS ESI (+) m/z 489, M+H.

Example 23: CD73 Enzyme Assay

Enzyme assays were carried out using an EnzChek® Pyrophosphate Assay Kit(E-6645 Molecular Probes) containing PNP (purine ribonucleosidephosphorylase) at 100 U/mL Stock and MESG(2-amino-6-mercapto-7-methylpurine) at 1 mM Stock. Human CD73 (0.25 nMfinal concentration in assay), MW 61000 expressed in CHO cells waspurchased from R&D Systems.

A compound of the present disclosure (5 μL) was transferred to a384-well assay plate. Compound was added in a 15 point, 3-fold serialdilution (300 μM to 0.0002 μM) in DMSO. CD73 assay buffer (25 mM HEPES,pH 7.5, 100 mM NaCl, 0.001% Tween-20, 1 uM ZnCl₂, 10 units PNP, 0.1 mMMESG, 0.25 nM hCD73) was added and the resulting solution allowed toequilibrate for 10 minutes at room temperature. The enzyme reaction wasinitiated by adding 20 μL of 125 μM AMP (diluted 10:1 with buffercontaining 50% glycerol, 25 mM Tris, pH 7.5, 1 mM ZnCl₂) to a finalconcentration of 25 μM AMP. The plate was immediately placed in a platereader (Synergy 2 or Spark 10), and a reading taken every minute for 10to 20 minutes in a kinetic run at 360 nm. The linear portion of thecurve was used to determine the observed rate (initial velocity). Lowsignal controls containing 10 μM adenosine 5′-(α,β-methylene)diphosphateand high signal controls containing no compound were measured for eachplate.

IC₅₀ values were calculated using Dotmatics template equation for4-parameter fit. Results are expressed as % inhibition using thefollowing equation:

${\% \mspace{14mu} {inhibition}} = {\left( \frac{{{high}\mspace{14mu} {control}} - {sample}}{{{high}\mspace{14mu} {control}} - {{low}\mspace{14mu} {control}}} \right) \times 100}$

The IC₅₀ of adenosine 5′-(α,β-methylene)diphosphate was 0.050 μM.

Example 24: CD73 Cell-Based Assay

U138 human neuroglioma cells were used in these experiments. U138 cellswere obtained from ATCC and cultured in DMEM with 10% FBS. 2500 cellswere seeded into 96-well plate with 100 μL of media the day before theexperiment. Cells were washed twice with 200 μL of assay buffer (20 mMHEPES, pH 7.4; 137 mM NaCl; 5.4 mM KCl; 1.3 mM CaCl₂; 4.2 mM NaHCO₃; 1mg/mL glucose) to remove residual inorganic phosphate. After washing,100 μL of buffer was added to each well, then 100 μL of a mixture of AMPsubstrate (200 μM) and diluted compound was added to each well. Thecells were incubated at 37° C. (with 5% CO₂) for 2 hours. 50 μL ofsupernatant was transferred to a 96-well assay plate and theconcentration of inorganic phosphate was determined using malachitegreen reagent (R&D System; Cat: DY996).

Table 2 shows biological activities of selected compounds describedherein in the enzyme and cell-based assays. Compound numbers correspondto the numbers and structures provided in Table 1 and Examples 1-22.

TABLE 2 ≥10 nM ≥100 nM Assay <10 nM (++++) <100 nM (+++) <1,000 nM (++)≥1,000 nM (+) CD73 Cell- 61, 62, 67, 69, 3, 20, 21, 36, 49, 4, 15, 16,18, 32, 1, 9, 12, 46, 55, Based assay 70, 71, 72, 73, 54, 56, 60, 68,43, 52, 57, 86, 133, 187, 199, IC₅₀ (nM) 78, 80, 81, 82, 74, 75, 76, 77,96, 160, 184, 206, 304 83, 84, 85, 87, 79, 93, 95, 98, 188, 207, 209,88, 89, 90, 91, 99, 100, 107, 211, 222, 248, 92, 94, 97, 101, 108, 112,113, 254, 283, 297 102, 103, 104, 115, 120, 122, 105, 106, 109, 127,128, 129, 110, 111, 114, 130, 132, 134, 116, 117, 119, 135, 139, 143,121, 123, 124, 145, 146, 152, 125, 126, 131, 153, 162, 163, 136, 137,138, 175, 176, 186, 140, 141, 142, 191, 193, 200, 144, 147, 154, 202,203, 212, 155, 156, 157, 213, 218, 219, 158, 159, 161, 231, 232, 239,164, 167, 168, 247, 250, 260, 169, 170, 171, 262, 265, 284, 172, 173,174, 288, 293, 303, 177, 178, 179, 305 180, 181, 182, 183, 189, 190,192, 194, 195, 196, 197, 198, 201, 204, 205, 229, 230, 240, 243, 244,252, 253, 255, 256, 257, 258, 261, 263, 266, 267, 269, 270, 271, 272,274, 275, 276, 279, 280, 285, 287, 289, 290, 291, 292, 294, 295, 296,298, 299, 300, 307, 308 CD73 Enzyme 4, 60, 61, 62, 69, 15, 16, 20, 21,3, 8, 9, 10, 12, 1, 2, 5, 6, 7, 11, Assay IC₅₀ (nM) 70, 71, 72, 73, 36,49, 54, 56, 18, 22, 29, 32, 13, 14, 17, 19, 74, 75, 76, 79, 67, 68, 77,78, 34, 35, 40, 43, 23, 24, 25, 26, 80, 81, 83, 84, 82, 95, 97, 98, 45,50, 51, 52, 27, 28, 30, 31, 85, 87, 88, 89, 99, 100, 104, 55, 57, 86,96, 33, 37, 38, 39, 90, 91, 92, 93, 107, 108, 112, 118, 120, 135, 41,42, 44, 46, 94, 101, 102, 113, 114, 117, 145, 146, 160, 47, 48, 53, 58,103, 105, 106, 121, 122, 126, 165, 203, 207, 59, 63, 64, 65, 109, 110,111, 127, 128, 129, 209, 210, 211, 66, 133, 148, 115, 116, 119, 130,137, 147, 217, 222, 234, 149, 150, 151, 123, 124, 125, 152, 162, 163,238, 241, 245, 166, 184, 185, 131, 132, 134, 175, 176, 193, 248, 254,259, 187, 199, 208, 136, 138, 139, 200, 202, 206, 264, 297 214, 215,216, 140, 141, 142, 212, 213, 218, 220, 223, 224, 143, 144, 153, 219,225, 231, 226, 227, 228, 154, 155, 156, 232, 237, 247, 242, 246, 302,157, 158, 159, 250, 258, 260, 304 161, 164, 167, 262, 265, 269, 168,169, 170, 272, 283, 284, 171, 172, 173, 288, 293, 294, 174, 177, 178,300, 303, 305, 179, 180, 181, 307 182, 183, 186, 188, 189, 190, 191,192, 194, 195, 196, 197, 198, 201, 204, 205, 229, 230, 233, 240, 243,244, 252, 253, 255, 256, 257, 261, 263, 266, 267, 270, 271, 274, 275,276, 279, 280, 282, 285, 287, 289, 290, 291, 292, 295, 296, 298, 299,308

What is claimed is:
 1. A compound of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein: W¹ is selectedfrom N, NR⁸, CR⁶, and S; W² and W³ are each independently selected fromN and CR⁶; W⁴ and W⁵ are each independently selected from N and C; W⁶ isselected from N, CR⁶, and S; wherein at least one of W¹, W², W³, W⁴, W⁵,and W⁶ is N, and provided that: when W¹, W², W³, W⁵, and W⁶ are N, W⁴ isnot N; and when either W¹ or W⁶ is S, the other is CR⁶; R¹⁵ is selectedfrom —NR¹R², —OR¹, —SR¹ and —CN; and C₃₋₁₂ membered carbocycle and 3- to12-membered heterocycle, each of which is optionally substituted withone or more R⁷; R¹ is selected from hydrogen; and C₁₋₆ alkyl and C₃₋₁₂carbocycle, each of which is optionally substituted with one or more R⁷;R² is selected from C₁₋₆ alkyl, C₃₋₁₂ carbocycle, 3- to 12-memberedheterocycle and benzyl, each of which is optionally substituted with oneor more R⁷; or R¹ and R² are taken together with the nitrogen atom towhich they are attached to form a 3- to 12-membered heterocycle,optionally substituted with one or more R⁷; R³ is selected fromhydrogen, halogen, cyano, —N(R⁸)₂ and —OR⁸; and C₁₋₆ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, 3- to 12-membered heterocycleand benzyl, each of which is optionally substituted with one or more R⁷;A is selected from —O—, —S—, —S(═O)— and —S(═O)₂—; X and Y areindependently selected from —O— and —NR⁸—; R⁴ and R⁵ are independentlyselected from: hydrogen; and C₁₋₆ alkyl, phenyl, and 3- to 12-memberedheterocycle, each of which is independently optionally substituted ateach occurrence with one or more substituents selected from halogen,—NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸,—S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂,—NR⁸S(═O)₂NR⁹R¹⁰, —S—S—R⁸, —S—C(O)R⁸, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,—OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,—NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,—P(O)(R⁸)₂, —OP(O)(OR⁸)₂, ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle; or R⁴ and R⁵ are taken together with the atomsto which they are attached to form a 3- to 12-membered heterocycle,optionally substituted with one or more R⁷; R⁶ is selected fromhydrogen, halogen and cyano; and C₁₋₆ alkyl, optionally substituted withone or more R⁷; R⁷ is independently selected at each occurrence from:halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸,—S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂,—NR⁸S(═O)₂NR⁹R¹⁰, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,—OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰,—C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂, —P(O)(R⁸)₂, ═O, ═S, and ═N(R⁸);C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂,—NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰,—NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —C(O)R⁸, —C(O)OR⁸,—OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸,—NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰,—P(O)(OR⁸)₂, —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle; and C₃₋₁₂ carbocycle and 3- to 12-memberedheterocycle, wherein each C₃₋₁₂ carbocycle and 3- to 12-memberedheterocycle in R⁷ is independently optionally substituted with one ormore substituents selected from halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂,—NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰,—NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —C(O)R⁸, —C(O)OR⁸,—OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸,—NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰,—P(O)(OR⁸)₂, —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl; R⁸ is independently selected at eachoccurrence from hydrogen; and C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl,1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle, each of which is optionally substituted by halogen, —CN,—NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂carbocycle, or 3- to 6-membered heterocycle; R⁹ and R¹⁰ are takentogether with the nitrogen atom to which they are attached to form aheterocycle, optionally substituted with one or more R⁷; R¹³ is selectedfrom hydrogen and C₁₋₆ alkyl; and R¹⁴ is selected from hydrogen and R⁷.2. The compound of claim 1, wherein W⁵ is N.
 3. The compound of claim 1,wherein W⁵ is C.
 4. The compound of claim 3, wherein one of W¹ or W⁶ isS.
 5. The compound of claim 3, wherein W⁴ is N.
 6. The compound of anyone of claims 1 to 5, wherein R¹³ is hydrogen.
 7. The compound of anyone of claims 1 to 6, wherein R¹⁴ is selected from hydrogen and phenyl.8. The compound of any one of claims 1 to 7, wherein R¹⁵ is —NR¹R². 9.The compound of any one of claims 1 to 8, wherein A is —O—.
 10. Thecompound of any one of claims 1 to 8, wherein A is selected from —S—,—S(═O)— and —S(═O)₂—.
 11. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein: W¹, W² and W³are each independently selected from N and CR⁶, wherein at least one ofW¹, W² and W³ is N; R¹ is selected from hydrogen; and C₁₋₆ alkyl andC₃₋₁₂ carbocycle, each of which is optionally substituted with one ormore R⁷; R² is selected from C₁₋₆ alkyl, C₃₋₁₂ carbocycle, 3- to12-membered heterocycle and benzyl, each of which is optionallysubstituted with one or more R⁷; or R¹ and R² are taken together withthe nitrogen atom to which they are attached to form a 3- to 12-memberedheterocycle, optionally substituted with one or more R⁷; R³ is selectedfrom hydrogen, halogen and cyano; and C₁₋₆ alkyl, C₃₋₁₂ carbocycle, 3-to 12-membered heterocycle and benzyl, each of which is optionallysubstituted with one or more R⁷; A is selected from —S—, —S(═O)— and—S(═O)₂—; X and Y are independently selected from —O— and —NR⁸—; R⁴ andR⁵ are independently selected from: hydrogen; and C₁₋₆ alkyl and phenyl,each of which is independently optionally substituted at each occurrencewith one or more substituents selected from halogen, —NO₂, —CN, —OR⁸,—SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,—S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,—S—S—R⁸, —S—C(O)R⁸, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸,—OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂,—NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂, —P(O)(R⁸)₂,—OP(O)(OR⁸)₂, ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle; R⁶ is selected from hydrogen, halogen and cyano; and C₁₋₆alkyl, optionally substituted with one or more R⁷; R⁷ is independentlyselected at each occurrence from: halogen, —NO₂, —CN, —OR⁸, —SR⁸,—N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰,—NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —C(O)R⁸, —C(O)OR⁸,—OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸,—NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰,—P(O)(OR⁸)₂, —P(O)(R⁸)₂, ═O, ═S, and ═N(R⁸); C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,and C₂₋₁₀ alkynyl, each of which is independently optionally substitutedat each occurrence with one or more substituents selected from halogen,—NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸,—S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂,—NR⁸S(═O)₂NR⁹R¹⁰, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂,—OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰,—C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂, —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle; and C₃₋₁₂ carbocycle and3- to 12-membered heterocycle, wherein each C₃₋₁₂ carbocycle and 3- to12-membered heterocycle in R⁷ is independently optionally substitutedwith one or more substituents selected from halogen, —NO₂, —CN, —OR⁸,—SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,—S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,—C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰,—NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂,—C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂, —P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; R⁸ is independently selectedat each occurrence from hydrogen; and C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, each of which is optionally substituted byhalogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃,C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle; and R⁹ and R¹⁰ aretaken together with the nitrogen atom to which they are attached to forma heterocycle, optionally substituted with one or more R⁷.
 12. Acompound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: W¹, W² and W³are each independently selected from N and CR⁶, wherein at least one ofW¹, W² and W³ is N; R¹ is selected from hydrogen; and C₁₋₆ alkyl andC₃₋₁₂ carbocycle, each of which is optionally substituted with one ormore R⁷; R² is selected from C₁₋₆ alkyl, C₃₋₁₂ carbocycle, 3- to12-membered heterocycle and benzyl, each of which is optionallysubstituted with one or more R⁷; or R¹ and R² are taken together withthe nitrogen atom to which they are attached to form a 3- to 12-memberedheterocycle, optionally substituted with one or more R⁷; R³ is selectedfrom halogen and cyano; and C₁₋₆ alkyl, C₃₋₁₂ carbocycle, 3- to12-membered heterocycle and benzyl, each of which is optionallysubstituted with one or more R⁷; X and Y are independently selected from—O— and —NR⁸—; R⁴ and R⁵ are independently selected from: hydrogen; andC₁₋₆ alkyl and phenyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, —NO₂, —CN, —OR, —SR, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸,—S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂,—NR⁸S(═O)₂NR⁹R¹⁰, —S—S—R⁸, —S—C(O)R⁸, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,—OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,—NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,—P(O)(R⁸)₂, —OP(O)(OR⁸)₂, ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle; R⁶ is selected from hydrogen, halogen andcyano; and C₁₋₆ alkyl, optionally substituted with one or more R⁷; R⁷ isindependently selected at each occurrence from: halogen, —NO₂, —CN,—OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰, —S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂,—S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸, —NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰,—C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰,—NR⁸C(O)R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂,—C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂, —P(O)(R⁸)₂, ═O, ═S, and ═N(R⁸); C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is independentlyoptionally substituted at each occurrence with one or more substituentsselected from halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰,—S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,—NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,—OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,—NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,—P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle; and C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle in R⁷ isindependently optionally substituted with one or more substituentsselected from halogen, —NO₂, —CN, —OR⁸, —SR⁸, —N(R⁸)₂, —NR⁹R¹⁰,—S(═O)R⁸, —S(═O)₂R⁸, —S(═O)₂N(R⁸)₂, —S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂R⁸,—NR⁸S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂NR⁹R¹⁰, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,—OC(O)OR⁸, —OC(O)N(R⁸)₂, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁸, —NR⁸C(O)OR⁸,—NR⁸C(O)N(R⁸)₂, —NR⁸C(O)NR⁹R¹⁰, —C(O)N(R⁸)₂, —C(O)NR⁹R¹⁰, —P(O)(OR⁸)₂,—P(O)(R⁸)₂, ═O, ═S, ═N(R⁸), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl; R⁸ is independently selected at each occurrence fromhydrogen; and C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to6-membered heteroalkyl, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle, each of which is optionally substituted by halogen, —CN,—NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂carbocycle, or 3- to 6-membered heterocycle; and R⁹ and R¹⁰ are takentogether with the nitrogen atom to which they are attached to form aheterocycle, optionally substituted with one or more R⁷.
 13. Thecompound of any one of the preceding claims, wherein R¹ and R² are takentogether with the nitrogen atom to which they are attached to form a 3-to 12-membered heterocycle, optionally substituted with one or more R⁷.14. The compound of claim 13, wherein R¹ and R² are taken together withthe nitrogen atom to which they are attached to form a 3- to 12-memberedheterocycle, optionally substituted with one or more substituentsindependently selected from halogen, —CN, C₁₋₄ alkyl, C₁₋₃ haloalkyl,—OH and —NH₂.
 15. The compound of any one of the preceding claims,wherein R¹ and R² are taken together with the nitrogen atom to whichthey are attached to form optionally substituted 3- to 7-memberedmonocyclic heterocycloalkyl or optionally substituted 5- to 12-memberedfused bicyclic heterocycloalkyl.
 16. The compound of any one of claims 1to 12, wherein R² is selected from C₁₋₆ alkyl, C₃₋₁₂ carbocycle, 3- to12-membered heterocycle and benzyl, each of which is optionallysubstituted with one or more substituents independently selected fromhalogen, —CN, C₁₋₄ alkyl, C₁₋₃ haloalkyl, —OH and —NH₂.
 17. The compoundof any one of claims 1 to 12, wherein R² is benzyl, optionallysubstituted with one or more R⁷.
 18. The compound of claim 17, whereinR² is benzyl, optionally substituted with one or more substituentsindependently selected from halogen, —CN, C₁₋₄ alkyl, C₁₋₃ haloalkyl,—OH and —NH₂.
 19. The compound of any one of claims 1 to 10, representedby Formula (III-A) or (III-B):

or a pharmaceutically acceptable salt thereof, wherein: R¹¹ is selectedfrom C₁₋₆ alkyl and C₃₋₁₂ carbocycle, each of which is optionallysubstituted with one or more R⁷; R¹² is independently selected at eachoccurrence from R⁷; and n is an integer from 0 to
 3. 20. The compound ofclaim 11, represented by Formula (II-A) or (II-B):

or a pharmaceutically acceptable salt thereof, wherein: R¹¹ is selectedfrom C₁₋₆ alkyl and C₃₋₁₂ carbocycle, each of which is optionallysubstituted with one or more R⁷; R¹² is independently selected at eachoccurrence from R⁷; and n is an integer from 0 to
 3. 21. The compound ofclaim 12, represented by Formula (I-A) or (I-B):

or a pharmaceutically acceptable salt thereof, wherein: R¹¹ is selectedfrom C₁₋₆ alkyl and C₃₋₁₂ carbocycle, each of which is optionallysubstituted with one or more R⁷; R¹² is independently selected at eachoccurrence from R⁷; and n is an integer from 0 to
 3. 22. The compound ofany one of claims 19 to 21, wherein R¹¹ is C₁₋₄ alkyl.
 23. The compoundof claim 22, wherein R¹¹ is selected from methyl, ethyl, iso-propyl andtert-butyl.
 24. The compound of any one of claims 19 to 21, wherein R¹¹is selected from C₁₋₄ alkyl and C₃₋₁₂ cycloalkyl, each of which isoptionally substituted with one or more R⁷.
 25. The compound of any oneof claims 19 to 24, wherein R¹² is independently selected at eachoccurrence from halogen, —CN, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkyland C₁₋₄ haloalkyl.
 26. The compound of any one of claims 19 to 25,wherein R¹² is independently selected at each occurrence from halogen,—CN, C₁₋₄ alkyl and C₁₋₄ haloalkyl.
 27. The compound of any one ofclaims 19 to 26, wherein R¹² is independently selected at eachoccurrence from F, —CN, —CH₃ and —CF₃.
 28. The compound of any one ofclaims 19 to 27, wherein n is an integer from 1 to
 3. 29. The compoundof any one of claims 1 to 10, represented by Formula (III-C):

or a pharmaceutically acceptable salt thereof, wherein: Z is selectedfrom C₃₋₁₂ cycloalkyl and 3- to 12-membered heterocycloalkyl, each ofwhich is optionally substituted with one or more R⁷.
 30. The compound ofclaim 11, represented by Formula (II-C):

or a pharmaceutically acceptable salt thereof, wherein: Z is selectedfrom C₃₋₁₂ cycloalkyl and 3- to 12-membered heterocycloalkyl, each ofwhich is optionally substituted with one or more R⁷.
 31. The compound ofclaim 12, represented by Formula (I-C):

or a pharmaceutically acceptable salt thereof, wherein: Z is selectedfrom C₃₋₁₂ cycloalkyl and 3- to 12-membered heterocycloalkyl, each ofwhich is optionally substituted with one or more R⁷.
 32. The compound ofany one of claims 29 to 31, wherein Z is selected from C₃₋₁₂ monocycliccycloalkyl or C₅₋₁₂ fused bicyclic cycloalkyl, each of which isoptionally substituted with one or more R⁷.
 33. The compound of claim32, wherein Z is C₅₋₁₂ fused bicyclic cycloalkyl, optionally substitutedwith one or more R⁷.
 34. The compound of any one of claims 29 to 33,wherein Z is substituted with one or more substituents independentlyselected from halogen, —CN, C₁₋₄ alkyl and C₁₋₃ haloalkyl.
 35. Thecompound of any one of claims 1 to 12 or 16 to 34, wherein R¹ isselected from hydrogen and —CH₃.
 36. The compound of any one of thepreceding claims, wherein W³ is N.
 37. The compound of any one of thepreceding claims, wherein W² is N or CH.
 38. The compound of claim 37,wherein W² is N.
 39. The compound of any one of the preceding claims,wherein W¹ is N or CH.
 40. The compound of claim 39, wherein W¹ is N.41. The compound of any one of claims 1 to 35, wherein W¹ is N or CH, W²is N and W³ is N.
 42. The compound of any one of claims 1 to 11, 19, 20,29 or 30, wherein R³ is selected from halogen and cyano; and C₁₋₆ alkyl,C₃₋₁₂ carbocycle, 3- to 12-membered heterocycle and benzyl, each ofwhich is optionally substituted with one or more R⁷.
 43. The compound ofany one of claims 1 to 11, 19, 20, 29 or 30, wherein R³ is selected fromhydrogen, halogen, —CN, C₁₋₃ alkyl and C₁₋₃ haloalkyl.
 44. The compoundof any one of the preceding claims, wherein R³ is selected from halogen,—CN, C₁₋₃ alkyl and C₁₋₃ haloalkyl.
 45. The compound of claim 44,wherein R³ is selected from —Cl and —CN.
 46. The compound of any one ofclaims 1 to 45, wherein at least one of R⁴ and R⁵ is C₁₋₆ alkyl,optionally substituted at each occurrence with one or more substituentsselected from halogen, —OR⁸, —S—S—R⁸, —S—C(O)R⁸, —OC(O)R⁸, —OC(O)OR⁸ and—P(O)(OR⁸)₂.
 47. The compound of any one of claims 1 to 45, wherein R⁴and R⁵ are independently selected from C₁₋₆ alkyl, optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, —OR, —S—S—R⁸, —S—C(O)R⁸, —OC(O)R⁸, —OC(O)OR⁸ and—P(O)(OR⁸)₂.
 48. The compound of any one of claims 1 to 45, wherein R⁴and R⁵ are independently selected from hydrogen and C₁₋₆ alkyl, whereinthe C₁₋₆ alkyl is optionally substituted at each occurrence with one ormore substituents selected from halogen, —OR⁸, —S—S—R⁸, —S—C(O)R⁸,—OC(O)R⁸, —OC(O)OR⁸ and —P(O)(OR⁸)₂.
 49. The compound of any one ofclaims 1 to 45, wherein R⁴ and R⁵ are independently selected from—CH₂OC(O)R⁸ and —CH₂OC(O)OR⁸.
 50. The compound of claim 47, wherein R⁴and R⁵ are independently selected from —CH₂OC(O)C(CH₃)₃,—CH₂OC(O)OCH(CH₃)₂, —CH₂OC(O)CH₃, —CH₂CH₂—S—S—(CH₂)₂OH and—CH₂CH₂—S—C(O)CH₃.
 51. The compound of any one of claims 1 to 45,wherein: R⁴ is phenyl, optionally substituted with —OR⁸; R⁵ is C₁₋₆alkyl substituted with one or more substituents selected from —OC(O)R⁸,—C(O)OR⁸, and —OC(O)OR⁸; and R⁸ is C₁₋₆ alkyl.
 52. The compound of anyone of claims 1 to 51, wherein X and Y are each —O—.
 53. The compound ofany one of claims 1 to 51, wherein one of X and Y is —O— and the otherone of X and Y is —NR⁸—.
 54. The compound of any one of the precedingclaims, wherein: W¹ is selected from N and CR⁶; W² is selected from Nand CH; W³ is N; R¹ is selected from hydrogen and C₁₋₄ alkyl; R³ isselected from halogen and cyano; and R⁶ is selected from hydrogen,halogen, cyano and C₁₋₄ alkyl.
 55. The compound of any one of thepreceding claims, wherein: W¹ is selected from N and CR⁶; W² is selectedfrom N and CH; W³ is N; R¹ is selected from hydrogen and C₁₋₄ alkyl; R³is selected from halogen and cyano; and R⁶ is selected from halogen,cyano and C₁₋₄ alkyl.
 56. The compound of any one of the precedingclaims, wherein —X—R⁴ and —Y—R⁵ are each —OH.
 57. The compound of anyone of claims 1 to 10, wherein R³ is selected from optionallysubstituted C₂-alkynyl and —OR⁸.
 58. The compound of claim 57, whereinR³ is selected from


59. The compound of any one of claims 1 to 10, wherein: W¹ is selectedfrom N and CR⁶; W² is selected from N and CH; W³ is N; W⁴ is C; W⁵ is N;W⁶ is CH; R¹ is selected from hydrogen and C₁₋₄ alkyl; R³ is selectedfrom halogen and cyano; and R⁶ is selected from hydrogen, halogen, cyanoand C₁₋₄ alkyl.
 60. The compound of any one of claims 1 to 10, wherein:W¹ is CH; W² is N; W³ is N; W⁴ is C; W⁵ is N; W⁶ is CH; R¹ is selectedfrom hydrogen; R² is C₃₋₁₂ carbocycle; and R³ is selected fromoptionally substituted C₂-alkynyl and —OR⁸.
 61. A substantially purestereoisomer of the compound of any one of the preceding claims.
 62. Thestereoisomer of claim 61, wherein the stereoisomer is provided in atleast 90% diastereomeric excess.
 63. A compound selected from Table 1.64. A pharmaceutical composition comprising a compound or salt of anyone of the preceding claims and a pharmaceutically acceptable carrier ordiluent.
 65. A method of inhibiting CD73-catalyzed hydrolysis ofadenosine monophosphate, comprising contacting CD73 with an effectiveamount of the compound of any one of claims 1 to
 63. 66. The method ofclaim 65, wherein the contacting comprising contacting a cell thatexpresses CD73.
 67. The method of claim 65 or 66, wherein the contactingtakes place in vivo.